Sample records for accelerated aging phenotype

  1. Redefining Aging in HIV Infection Using Phenotypes.

    PubMed

    Stoff, David M; Goodkin, Karl; Jeste, Dilip; Marquine, Maria

    2017-10-01

    This article critically reviews the utility of "phenotypes" as behavioral descriptors in aging/HIV research that inform biological underpinnings and treatment development. We adopt a phenotypic redefinition of aging conceptualized within a broader context of HIV infection and of aging. Phenotypes are defined as dimensions of behavior, closely related to fundamental mechanisms, and, thus, may be more informative than chronological age. Primary emphasis in this review is given to comorbid aging and cognitive aging, though other phenotypes (i.e., disability, frailty, accelerated aging, successful aging) are also discussed in relation to comorbid aging and cognitive aging. The main findings that emerged from this review are as follows: (1) the phenotypes, comorbid aging and cognitive aging, are distinct from each other, yet overlapping; (2) associative relationships are the rule in HIV for comorbid and cognitive aging phenotypes; and (3) HIV behavioral interventions for both comorbid aging and cognitive aging have been limited. Three paths for research progress are identified for phenotype-defined aging/HIV research (i.e., clinical and behavioral specification, biological mechanisms, intervention targets), and some important research questions are suggested within each of these research paths.

  2. Poor maternal nutrition and accelerated postnatal growth induces an accelerated aging phenotype and oxidative stress in skeletal muscle of male rats

    PubMed Central

    Fernandez-Twinn, Denise S.; Chen, Jian Hua; Hargreaves, Iain P.; Neergheen, Viruna; Aiken, Catherine E.; Ozanne, Susan E.

    2016-01-01

    ABSTRACT ‘Developmental programming’, which occurs as a consequence of suboptimal in utero and early environments, can be associated with metabolic dysfunction in later life, including an increased incidence of cardiovascular disease and type 2 diabetes, and predisposition of older men to sarcopenia. However, the molecular mechanisms underpinning these associations are poorly understood. Many conditions associated with developmental programming are also known to be associated with the aging process. We therefore utilized our well-established rat model of low birth weight and accelerated postnatal catch-up growth (termed ‘recuperated’) in this study to establish the effects of suboptimal maternal nutrition on age-associated factors in skeletal muscle. We demonstrated accelerated telomere shortening (a robust marker of cellular aging) as evidenced by a reduced frequency of long telomeres (48.5-8.6 kb) and an increased frequency of short telomeres (4.2-1.3 kb) in vastus lateralis muscle from aged recuperated offspring compared to controls. This was associated with increased protein expression of the DNA-damage-repair marker 8-oxoguanine-glycosylase (OGG1) in recuperated offspring. Recuperated animals also demonstrated an oxidative stress phenotype, with decreased citrate synthase activity, increased electron-transport-complex activities of complex I, complex II-III and complex IV (all markers of functional mitochondria), and increased xanthine oxidase (XO), p67phox and nuclear-factor kappa-light-chain-enhancer of activated B-cells (NF-κB). Recuperated offspring also demonstrated increased antioxidant defense capacity, with increased protein expression of manganese superoxide dismutase (MnSOD), copper-zinc superoxide dismutase (CuZnSOD), catalase and heme oxygenase-1 (HO1), all of which are known targets of NF-κB and can be upregulated as a consequence of oxidative stress. Recuperated offspring also had a pro-inflammatory phenotype, as evidenced by

  3. Epigenetic Age Acceleration Assessed with Human White-Matter Images.

    PubMed

    Hodgson, Karen; Carless, Melanie A; Kulkarni, Hemant; Curran, Joanne E; Sprooten, Emma; Knowles, Emma E; Mathias, Samuel; Göring, Harald H H; Yao, Nailin; Olvera, Rene L; Fox, Peter T; Almasy, Laura; Duggirala, Ravi; Blangero, John; Glahn, David C

    2017-05-03

    The accurate estimation of age using methylation data has proved a useful and heritable biomarker, with acceleration in epigenetic age predicting a number of age-related phenotypes. Measures of white matter integrity in the brain are also heritable and highly sensitive to both normal and pathological aging processes across adulthood. We consider the phenotypic and genetic interrelationships between epigenetic age acceleration and white matter integrity in humans. Our goal was to investigate processes that underlie interindividual variability in age-related changes in the brain. Using blood taken from a Mexican-American extended pedigree sample ( n = 628; age = 23.28-93.11 years), epigenetic age was estimated using the method developed by Horvath (2013). For n = 376 individuals, diffusion tensor imaging scans were also available. The interrelationship between epigenetic age acceleration and global white matter integrity was investigated with variance decomposition methods. To test for neuroanatomical specificity, 16 specific tracts were additionally considered. We observed negative phenotypic correlations between epigenetic age acceleration and global white matter tract integrity (ρ pheno = -0.119, p = 0.028), with evidence of shared genetic (ρ gene = -0.463, p = 0.013) but not environmental influences. Negative phenotypic and genetic correlations with age acceleration were also seen for a number of specific white matter tracts, along with additional negative phenotypic correlations between granulocyte abundance and white matter integrity. These findings (i.e., increased acceleration in epigenetic age in peripheral blood correlates with reduced white matter integrity in the brain and shares common genetic influences) provide a window into the neurobiology of aging processes within the brain and a potential biomarker of normal and pathological brain aging. SIGNIFICANCE STATEMENT Epigenetic measures can be used to predict age with a high degree of accuracy and so

  4. Accelerated epigenetic aging in Werner syndrome.

    PubMed

    Maierhofer, Anna; Flunkert, Julia; Oshima, Junko; Martin, George M; Haaf, Thomas; Horvath, Steve

    2017-04-01

    Individuals suffering from Werner syndrome (WS) exhibit many clinical signs of accelerated aging. While the underlying constitutional mutation leads to accelerated rates of DNA damage, it is not yet known whether WS is also associated with an increased epigenetic age according to a DNA methylation based biomarker of aging (the "Epigenetic Clock"). Using whole blood methylation data from 18 WS cases and 18 age matched controls, we find that WS is associated with increased extrinsic epigenetic age acceleration (p=0.0072) and intrinsic epigenetic age acceleration (p=0.04), the latter of which is independent of age-related changes in the composition of peripheral blood cells. A multivariate model analysis reveals that WS is associated with an increase in DNA methylation age (on average 6.4 years, p=0.011) even after adjusting for chronological age, gender, and blood cell counts. Further, WS might be associated with a reduction in naïve CD8+ T cells (p=0.025) according to imputed measures of blood cell counts. Overall, this study shows that WS is associated with an increased epigenetic age of blood cells which is independent of changes in blood cell composition. The extent to which this alteration is a cause or effect of WS disease phenotypes remains unknown.

  5. Mutational robustness accelerates the origin of novel RNA phenotypes through phenotypic plasticity.

    PubMed

    Wagner, Andreas

    2014-02-18

    Novel phenotypes can originate either through mutations in existing genotypes or through phenotypic plasticity, the ability of one genotype to form multiple phenotypes. From molecules to organisms, plasticity is a ubiquitous feature of life, and a potential source of exaptations, adaptive traits that originated for nonadaptive reasons. Another ubiquitous feature is robustness to mutations, although it is unknown whether such robustness helps or hinders the origin of new phenotypes through plasticity. RNA is ideal to address this question, because it shows extensive plasticity in its secondary structure phenotypes, a consequence of their continual folding and unfolding, and these phenotypes have important biological functions. Moreover, RNA is to some extent robust to mutations. This robustness structures RNA genotype space into myriad connected networks of genotypes with the same phenotype, and it influences the dynamics of evolving populations on a genotype network. In this study I show that both effects help accelerate the exploration of novel phenotypes through plasticity. My observations are based on many RNA molecules sampled at random from RNA sequence space, and on 30 biological RNA molecules. They are thus not only a generic feature of RNA sequence space but are relevant for the molecular evolution of biological RNA. Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  6. Menopause accelerates biological aging

    PubMed Central

    Levine, Morgan E.; Lu, Ake T.; Chen, Brian H.; Hernandez, Dena G.; Singleton, Andrew B.; Ferrucci, Luigi; Bandinelli, Stefania; Salfati, Elias; Manson, JoAnn E.; Quach, Austin; Kusters, Cynthia D. J.; Kuh, Diana; Wong, Andrew; Teschendorff, Andrew E.; Widschwendter, Martin; Ritz, Beate R.; Absher, Devin; Assimes, Themistocles L.; Horvath, Steve

    2016-01-01

    Although epigenetic processes have been linked to aging and disease in other systems, it is not yet known whether they relate to reproductive aging. Recently, we developed a highly accurate epigenetic biomarker of age (known as the “epigenetic clock”), which is based on DNA methylation levels. Here we carry out an epigenetic clock analysis of blood, saliva, and buccal epithelium using data from four large studies: the Women's Health Initiative (n = 1,864); Invecchiare nel Chianti (n = 200); Parkinson's disease, Environment, and Genes (n = 256); and the United Kingdom Medical Research Council National Survey of Health and Development (n = 790). We find that increased epigenetic age acceleration in blood is significantly associated with earlier menopause (P = 0.00091), bilateral oophorectomy (P = 0.0018), and a longer time since menopause (P = 0.017). Conversely, epigenetic age acceleration in buccal epithelium and saliva do not relate to age at menopause; however, a higher epigenetic age in saliva is exhibited in women who undergo bilateral oophorectomy (P = 0.0079), while a lower epigenetic age in buccal epithelium was found for women who underwent menopausal hormone therapy (P = 0.00078). Using genetic data, we find evidence of coheritability between age at menopause and epigenetic age acceleration in blood. Using Mendelian randomization analysis, we find that two SNPs that are highly associated with age at menopause exhibit a significant association with epigenetic age acceleration. Overall, our Mendelian randomization approach and other lines of evidence suggest that menopause accelerates epigenetic aging of blood, but mechanistic studies will be needed to dissect cause-and-effect relationships further. PMID:27457926

  7. Age is associated with asthma phenotypes.

    PubMed

    Ponte, Eduardo V; Lima, Aline; Almeida, Paula C A; de Jesus, Juliana P V; Lima, Valmar B; Scichilone, Nicola; Souza-Machado, Adelmir; Cruz, Álvaro A

    2017-11-01

    The relationship between age and asthma phenotypes is important as population is ageing, asthma is becoming common in older ages and recently developed treatments for asthma are guided by phenotypes. The aim of this study is to evaluate whether age is associated with specific asthma phenotypes. This is a cross-sectional study. We included subjects with asthma of varied degrees of severity. Subjects underwent spirometry, skin prick test to aeroallergens, answered the Asthma Control Questionnaire and had blood samples collected. We performed binary logistic regression analysis to evaluate whether age is associated with asthma phenotypes. We enrolled 868 subjects. In comparison with subjects ≤ 40 years, older subjects had high odds of irreversible airway obstruction (from 41 to 64 years, OR: 1.83 (95% CI: 1.32-2.54); ≥65 years, OR: 3.45 (2.12-5.60)) and severe asthma phenotypes (from 41 to 64 years, OR: 3.23 (2.26-4.62); ≥65 years, OR: 4.55 (2.39-8.67)). Older subjects had low odds of atopic (from 41 to 64 years, OR: 0.56 (0.39-0.79); ≥65 years, OR: 0.47 (0.27-0.84)) and eosinophilic phenotypes (from 41 to 64 years, OR: 0.63 (0.46-0.84); ≥65 years, OR: 0.39 (0.24-0.64)). Older subjects with asthma have low odds of atopic and eosinophilic phenotypes, whereas they present high odds of irreversible airway obstruction and severe asthma. © 2017 Asian Pacific Society of Respirology.

  8. Trajectories of the healthy ageing phenotype among middle-aged and older Britons, 2004-2013.

    PubMed

    Tampubolon, Gindo

    2016-06-01

    Since the ageing population demands a response to ensure older people remain healthy and active, we studied the dynamics of a recently proposed healthy ageing phenotype. We drew the phenotype's trajectories and tested whether their levels and rates of change are influenced by health behaviours, comorbidities and socioeconomic positions earlier in the life course. The English Longitudinal Ageing Study, a prospective, nationally representative sample of people aged ≥50 years, measured a set of eight biomarkers which make up the outcome of the healthy ageing phenotype three times over nearly a decade (N2004=5009, N2008=5301, N2013=4455). A cluster of health behaviours, comorbidities and socioeconomic positions were also measured repeatedly. We assessed the phenotype's distribution non-parametrically, then fitted linear mixed models to phenotypic change and further examined time interactions with gender and socioeconomic position. We ran additional analyses to test robustness. Women had a wider distribution of the healthy ageing phenotype than men had. The phenotype declined annually by -0.242 (95% confidence interval [CI]: -0.352, -0.131). However, there was considerable heterogeneity in the levels and rates of phenotypic change. Women started at higher levels, then declined more steeply by -0.293 (CI: -0.403, -0.183) annually, leading to crossover in the trajectories. Smoking and physical activity assessed on the Allied Dunbar scale were strongly associated with the trajectories. Though marked by secular decline, the trajectories of the healthy ageing phenotype showed distinct socioeconomic gradients. The trajectories were also susceptible to variations in health behaviours, strengthening the case for serial interventions to attain healthy and active ageing. Copyright © 2016 The Author. Published by Elsevier Ireland Ltd.. All rights reserved.

  9. DNA methylation age is not accelerated in brain or blood of subjects with schizophrenia.

    PubMed

    McKinney, Brandon C; Lin, Huang; Ding, Ying; Lewis, David A; Sweet, Robert A

    2017-10-05

    Individuals with schizophrenia (SZ) exhibit multiple premature age-related phenotypes and die ~20years prematurely. The accelerated aging hypothesis of SZ has been advanced to explain these observations, it posits that SZ-associated factors accelerate the progressive biological changes associated with normal aging. Testing the hypothesis has been limited by the absence of robust, meaningful, and multi-tissue measures of biological age. Recently, a method was described in which DNA methylation (DNAm) levels at 353 genomic sites are used to produce "DNAm age", an estimate of biological age with advantages over existing measures. We used this method and 3 publicly-available DNAm datasets, 1 from brain and 2 from blood, to test the hypothesis. The brain dataset was composed of data from the dorsolateral prefrontal cortex of 232 non-psychiatric control (NPC) and 195 SZ subjects. Blood dataset #1 was composed of data from whole blood of 304 NPC and 332 SZ subjects, and blood dataset #2 was composed of data from whole blood of 405 NPC and 260 SZ subjects. DNAm age and chronological age correlated strongly (r=0.92-0.95, p<0.0001) in both NPC and SZ subjects in all 3 datasets. DNAm age acceleration did not differ between NPC and SZ subjects in the brain dataset (t=0.52, p=0.60), blood dataset #1 (t=1.51, p=0.13), or blood dataset #2 (t=0.93, p=0.35). Consistent with our previous findings from a smaller study of postmortem brains, our findings suggest there is no acceleration of brain or blood aging in SZ and, thus, do not support the accelerated aging hypothesis of SZ. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Changing course in ageing research: The healthy ageing phenotype.

    PubMed

    Franco, Oscar H; Karnik, Kavita; Osborne, Gabrielle; Ordovas, Jose M; Catt, Michael; van der Ouderaa, Frans

    2009-05-20

    Ageing is often associated with the aged and the diseased, nevertheless ageing is a process that starts in-uterus and is characterised by a progressive functional loss but not necessarily by the presence of disease and poor quality of life. How to meander through life without crossing the confines of major chronic disease and cognitive and physical impairment remains one of the most relevant challenges for science and humankind. Delimiting that 'immaculate' trajectory - that we dub as the 'Healthy Ageing Phenotype' - and exploring solutions to help the population to stay or return to this trajectory should constitute the core focus of scientific research. Nevertheless, current efforts on ageing research are mainly focused on developing animal models to disentangle the human ageing process, and on age-related disorders often providing merely palliative solutions. Therefore, to identify alternative perspectives in ageing research, Unilever and the Medical Research Council (MRC) UK convened a Spark workshop entitled 'The Healthy Ageing Phenotype'. In this meeting, international specialists from complementary areas related to ageing research, gathered to find clear attributes and definitions of the 'Healthy Ageing Phenotype', to identify potential mechanisms and interventions to improve healthy life expectancy of the population; and to highlight areas within ageing research that should be prioritised in the future. General agreement was reached in recognising ageing research as a disaggregated field with little communication between basic, epidemiological and clinical areas of research and limited translation to society. A more holistic, multi-disciplinary approach emanating from a better understanding of healthy ageing trajectories and centred along human biological resilience, its maintenance and the reversibility from early deviations into pathological trajectories, is urgently required. Future research should concentrate on understanding the mechanisms that permit

  11. PTSD is associated with an increase in aged T cell phenotypes in adults living in Detroit

    PubMed Central

    Aiello, Allison E.; Dowd, Jennifer B.; Jayabalasingham, Bamini; Feinstein, Lydia; Uddin, Monica; Simanek, Amanda M.; Cheng, Caroline K.; Galea, Sandro; Wildman, Derek E.; Koenen, Karestan; Pawelec, Graham

    2016-01-01

    Background Psychosocial stress is thought to play a key role in the acceleration of immunological aging. This study investigated the relationship between lifetime and past-year history of post-traumatic stress disorder (PTSD) and the distribution of T cell phenotypes thought to be characteristic of immunological aging. Methods Data were from 85 individuals who participated in the community-based Detroit Neighborhood Health Study. Immune markers assessed included the CD4:CD8 ratio, the ratio of late-differentiated effector (CCR7-CD45RA+CD27-CD28-) to naïve (CCR7+CD45RA+CD27+CD28+) T cells, the percentage of KLRG1-expressing cells, and the percentage of CD57-expressing cells. Results In models adjusted for age, gender, race/ethnicity, education, smoking status, and medication use, we found that past-year PTSD was associated with statistically significant differences in the CD8+ T cell population, including a higher ratio of late-differentiated effector to naïve T cells, a higher percentage of KLRG1+ cells, and a higher percentage of CD57+ cells. The percentage of CD57+ cells in the CD4 subset was also significantly higher and the CD4:CD8 ratio significantly lower among individuals who had experienced past-year PTSD. Lifetime PTSD was also associated with differences in several parameters of immune aging. Conclusions PTSD is associated with an aged immune phenotype and should be evaluated as a potential catalyzer of accelerated immunological aging in future studies. PMID:26894484

  12. Loss of circadian clock accelerates aging in neurodegeneration-prone mutants.

    PubMed

    Krishnan, Natraj; Rakshit, Kuntol; Chow, Eileen S; Wentzell, Jill S; Kretzschmar, Doris; Giebultowicz, Jadwiga M

    2012-03-01

    Circadian clocks generate rhythms in molecular, cellular, physiological, and behavioral processes. Recent studies suggest that disruption of the clock mechanism accelerates organismal senescence and age-related pathologies in mammals. Impaired circadian rhythms are observed in many neurological diseases; however, it is not clear whether loss of rhythms is the cause or result of neurodegeneration, or both. To address this important question, we examined the effects of circadian disruption in Drosophila melanogaster mutants that display clock-unrelated neurodegenerative phenotypes. We combined a null mutation in the clock gene period (per(01)) that abolishes circadian rhythms, with a hypomorphic mutation in the carbonyl reductase gene sniffer (sni(1)), which displays oxidative stress induced neurodegeneration. We report that disruption of circadian rhythms in sni(1) mutants significantly reduces their lifespan compared to single mutants. Shortened lifespan in double mutants was coupled with accelerated neuronal degeneration evidenced by vacuolization in the adult brain. In addition, per(01)sni(1) flies showed drastically impaired vertical mobility and increased accumulation of carbonylated proteins compared to age-matched single mutant flies. Loss of per function does not affect sni mRNA expression, suggesting that these genes act via independent pathways producing additive effects. Finally, we show that per(01) mutation accelerates the onset of brain pathologies when combined with neurodegeneration-prone mutation in another gene, swiss cheese (sws(1)), which does not operate through the oxidative stress pathway. Taken together, our data suggest that the period gene may be causally involved in neuroprotective pathways in aging Drosophila. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. Loss of circadian clock accelerates aging in neurodegeneration-prone mutants

    PubMed Central

    Krishnan, Natraj; Rakshit, Kuntol; Chow, Eileen S.; Wentzell, Jill S.; Kretzschmar, Doris; Giebultowicz, Jadwiga M.

    2012-01-01

    Circadian clocks generate rhythms in molecular, cellular, physiological, and behavioral processes. Recent studies suggest that disruption of the clock mechanism accelerates organismal senescence and age-related pathologies in mammals. Impaired circadian rhythms are observed in many neurological diseases; however, it is not clear whether loss of rhythms is the cause or result of neurodegeneration, or both. To address this important question, we examined the effects of circadian disruption in Drosophila melanogaster mutants that display clock-unrelated neurodegenerative phenotypes. We combined a null mutation in the clock gene period (per01) that abolishes circadian rhythms, with a hypomorphic mutation in the carbonyl reductase gene sniffer (sni1), which displays oxidative stress induced neurodegeneration. We report that disruption of circadian rhythms in sni1 mutants significantly reduces their lifespan compared to single mutants. Shortened lifespan in double mutants was coupled with accelerated neuronal degeneration evidenced by vacuolization in the adult brain. In addition, per01 sni1 flies showed drastically impaired vertical mobility and increased accumulation of carbonylated proteins compared to age-matched single mutant flies. Loss of per function does not affect sni mRNA expression, suggesting that these genes act via independent pathways producing additive effects. Finally, we show that per01 mutation accelerates the onset of brain pathologies when combined with neurodegeneration-prone mutation in another gene, swiss cheese (sws1), which does not operate through the oxidative stress pathway. Taken together, our data suggest that the period gene may be causally involved in neuroprotective pathways in aging Drosophila. PMID:22227001

  14. Sod2 haploinsufficiency does not accelerate aging of telomere dysfunctional mice

    PubMed Central

    Guachalla, Luis Miguel; Ju, Zhenyu; Koziel, Rafal; von Figura, Guido; Song, Zhangfa; Fusser, Markus; Epe, Bernd; Jansen-Dűrr, Pidder; Rudolph, K. Lenhard

    2009-01-01

    Telomere shortening represents a causal factor of cellular senescence. At the same time, several lines of evidence indicate a pivotal role of oxidative DNA damage for the aging process in vivo. A causal connection between the two observations was suggested by experiments showing accelerated telomere shorting under conditions of oxidative stress in cultured cells, but has never been studied in vivo. We therefore have analysed whether an increase in mitochondrial derived oxidative stress in response to heterozygous deletion of superoxide dismutase (Sod2+/-) would exacerbate aging phenotypes in telomere dysfunctional (mTerc-/-) mice. Heterozygous deletion of Sod2 resulted in reduced SOD2 protein levels and increased oxidative stress in aging telomere dysfunctional mice, but this did not lead to an increase in basal levels of oxidative nuclear DNA damage, an accumulation of nuclear DNA breaks, or an increased rate of telomere shortening in the mice. Moreover, heterozygous deletion of Sod2 did not accelerate the depletion of stem cells and the impairment in organ maintenance in aging mTerc-/- mice. In agreement with these observations, Sod2 haploinsufficiency did not lead to a further reduction in lifespan of mTerc-/- mice. Together, these results indicate that a decrease in SOD2-dependent antioxidant defence does not exacerbate aging in the context of telomere dysfunction. PMID:20195488

  15. Accelerating root system phenotyping of seedlings through a computer-assisted processing pipeline.

    PubMed

    Dupuy, Lionel X; Wright, Gladys; Thompson, Jacqueline A; Taylor, Anna; Dekeyser, Sebastien; White, Christopher P; Thomas, William T B; Nightingale, Mark; Hammond, John P; Graham, Neil S; Thomas, Catherine L; Broadley, Martin R; White, Philip J

    2017-01-01

    There are numerous systems and techniques to measure the growth of plant roots. However, phenotyping large numbers of plant roots for breeding and genetic analyses remains challenging. One major difficulty is to achieve high throughput and resolution at a reasonable cost per plant sample. Here we describe a cost-effective root phenotyping pipeline, on which we perform time and accuracy benchmarking to identify bottlenecks in such pipelines and strategies for their acceleration. Our root phenotyping pipeline was assembled with custom software and low cost material and equipment. Results show that sample preparation and handling of samples during screening are the most time consuming task in root phenotyping. Algorithms can be used to speed up the extraction of root traits from image data, but when applied to large numbers of images, there is a trade-off between time of processing the data and errors contained in the database. Scaling-up root phenotyping to large numbers of genotypes will require not only automation of sample preparation and sample handling, but also efficient algorithms for error detection for more reliable replacement of manual interventions.

  16. Chronic inflammation as a determinant of future aging phenotypes.

    PubMed

    Akbaraly, Tasnime N; Hamer, Mark; Ferrie, Jane E; Lowe, Gordon; Batty, G David; Hagger-Johnson, Gareth; Singh-Manoux, Archana; Shipley, Martin J; Kivimäki, Mika

    2013-11-05

    The importance of chronic inflammation as a determinant of aging phenotypes may have been underestimated in previous studies that used a single measurement of inflammatory markers. We assessed inflammatory markers twice over a 5-year exposure period to examine the association between chronic inflammation and future aging phenotypes in a large population of men and women. We obtained data for 3044 middle-aged adults (28.2% women) who were participating in the Whitehall II study and had no history of stroke, myocardial infarction or cancer at our study's baseline (1997-1999). Interleukin-6 was measured at baseline and 5 years earlier. Cause-specific mortality, chronic disease and functioning were ascertained from hospital data, register linkage and clinical examinations. We used these data to create 4 aging phenotypes at the 10-year follow-up (2007-2009): successful aging (free of major chronic disease and with optimal physical, mental and cognitive functioning), incident fatal or nonfatal cardiovascular disease, death from noncardiovascular causes and normal aging (all other participants). Of the 3044 participants, 721 (23.7%) met the criteria for successful aging at the 10-year follow-up, 321 (10.6%) had cardiovascular disease events, 147 (4.8%) died from noncardiovascular causes, and the remaining 1855 (60.9%) were included in the normal aging phenotype. After adjustment for potential confounders, having a high interleukin-6 level (> 2.0 ng/L) twice over the 5-year exposure period nearly halved the odds of successful aging at the 10-year follow-up (odds ratio [OR] 0.53, 95% confidence interval [CI] 0.38-0.74) and increased the risk of future cardiovascular events (OR 1.64, 95% CI 1.15-2.33) and noncardiovascular death (OR 2.43, 95% CI 1.58-3.80). Chronic inflammation, as ascertained by repeat measurements, was associated with a range of unhealthy aging phenotypes and a decreased likelihood of successful aging. Our results suggest that assessing long-term chronic

  17. Accelerated and accentuated neurocognitive aging in HIV infection.

    PubMed

    Sheppard, David P; Iudicello, Jennifer E; Morgan, Erin E; Kamat, Rujvi; Clark, Lindsay R; Avci, Gunes; Bondi, Mark W; Woods, Steven Paul

    2017-06-01

    There is debate as to whether the neurocognitive changes associated with HIV infection represent an acceleration of the typical aging process or more simply reflect a greater accentuated risk for age-related declines. We aimed to determine whether accelerated neurocognitive aging is observable in a sample of older HIV-infected individuals compared to age-matched seronegatives and older old (i.e., aged ≥65) seronegative adults. Participants in a cross-sectional design included 48 HIV-seronegative (O-) and 40 HIV-positive (O+) participants between the ages of 50-65 (mean ages = 55 and 56, respectively) and 40 HIV-seronegative participants aged ≥65 (OO-; mean age = 74) who were comparable for other demographics. All participants were administered a brief neurocognitive battery of attention, episodic memory, speeded executive functions, and confrontation naming (i.e., Boston Naming Test). The O+ group performed more poorly than the O- group (i.e., accentuated aging), but not differently from the OO- on digit span and initial recall of a supraspan word list, consistent with an accelerating aging profile. However, the O+ group's performance was comparable to the O- group on all other neurocognitive tests (ps > 0.05). These data partially support a model of accelerated neurocognitive aging in HIV infection, which was observed in the domain of auditory verbal attention, but not in the areas of memory, language, or speeded executive functions. Future studies should examine whether HIV-infected adults over 65 evidence accelerated aging in downstream neurocognitive domains and subsequent everyday functioning outcomes.

  18. Priming of microglia in a DNA-repair deficient model of accelerated aging.

    PubMed

    Raj, Divya D A; Jaarsma, Dick; Holtman, Inge R; Olah, Marta; Ferreira, Filipa M; Schaafsma, Wandert; Brouwer, Nieske; Meijer, Michel M; de Waard, Monique C; van der Pluijm, Ingrid; Brandt, Renata; Kreft, Karim L; Laman, Jon D; de Haan, Gerald; Biber, Knut P H; Hoeijmakers, Jan H J; Eggen, Bart J L; Boddeke, Hendrikus W G M

    2014-09-01

    Aging is associated with reduced function, degenerative changes, and increased neuroinflammation of the central nervous system (CNS). Increasing evidence suggests that changes in microglia cells contribute to the age-related deterioration of the CNS. The most prominent age-related change of microglia is enhanced sensitivity to inflammatory stimuli, referred to as priming. It is unclear if priming is due to intrinsic microglia ageing or induced by the ageing neural environment. We have studied this in Ercc1 mutant mice, a DNA repair-deficient mouse model that displays features of accelerated aging in multiple tissues including the CNS. In Ercc1 mutant mice, microglia showed hallmark features of priming such as an exaggerated response to peripheral lipopolysaccharide exposure in terms of cytokine expression and phagocytosis. Specific targeting of the Ercc1 deletion to forebrain neurons resulted in a progressive priming response in microglia exemplified by phenotypic alterations. Summarizing, these data show that neuronal genotoxic stress is sufficient to switch microglia from a resting to a primed state. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Heart Failure as an Aging-Related Phenotype.

    PubMed

    Morita, Hiroyuki; Komuro, Issei

    2018-01-27

    The molecular pathophysiology of heart failure, which is one of the leading causes of mortality, is not yet fully understood. Heart failure can be regarded as a systemic syndrome of aging-related phenotypes. Wnt/β-catenin signaling and the p53 pathway, both of which are key regulators of aging, have been demonstrated to play a critical role in the pathogenesis of heart failure. Circulating C1q was identified as a novel activator of Wnt/β-catenin signaling, promoting systemic aging-related phenotypes including sarcopenia and heart failure. On the other hand, p53 induces the apoptosis of cardiomyocytes in the failing heart. In these molecular mechanisms, the cross-talk between cardiomyocytes and non-cardiomyocytes (e,g,. endothelial cells, fibroblasts, smooth muscle cells, macrophages) deserves mentioning. In this review, we summarize recent advances in the understanding of the molecular pathophysiology underlying heart failure, focusing on Wnt/β-catenin signaling and the p53 pathway.

  20. The effect of accelerated aging on the wear of UHMWPE.

    PubMed

    Sakoda, H; Fisher, J; Lu, S; Buchanan, F

    2001-01-01

    Oxidative degradation of UHMWPE has been found to be a cause of elevated wear rate of the polymer in total joint replacement leading to failure of these devices. In order to evaluate long term stability of polymers, various accelerated aging methods have been developed. In this study, wear rates of shelf aged UHMWPE and "accelerated aged" UHMWPE were compared using a multi-directional pin-on-plate wear test machine in order to evaluate the effect of the accelerated aging on wear. Wear factors of the aged materials were found to depend on their density, which is a measure of oxidation level. Finally, accelerated aging was calibrated against shelf aging in terms of wear rate. Copyright 2001 Kluwer Academic Publishers

  1. Hyper telomere recombination accelerates replicative senescence and may promote premature aging

    PubMed Central

    Hagelstrom, R. Tanner; Blagoev, Krastan B.; Niedernhofer, Laura J.; Goodwin, Edwin H.; Bailey, Susan M.

    2010-01-01

    Werner syndrome and Bloom syndrome result from defects in the RecQ helicases Werner (WRN) and Bloom (BLM), respectively, and display premature aging phenotypes. Similarly, XFE progeroid syndrome results from defects in the ERCC1-XPF DNA repair endonuclease. To gain insight into the origin of cellular senescence and human aging, we analyzed the dependence of sister chromatid exchange (SCE) frequencies on location [i.e., genomic (G-SCE) vs. telomeric (T-SCE) DNA] in primary human fibroblasts deficient in WRN, BLM, or ERCC1-XPF. Consistent with our other studies, we found evidence of elevated T-SCE in telomerase-negative but not telomerase-positive backgrounds. In telomerase-negative WRN-deficient cells, T-SCE—but not G-SCE—frequencies were significantly increased compared with controls. In contrast, SCE frequencies were significantly elevated in BLM-deficient cells irrespective of genome location. In ERCC1-XPF-deficient cells, neither T- nor G-SCE frequencies differed from controls. A theoretical model was developed that allowed an in silico investigation into the cellular consequences of increased T-SCE frequency. The model predicts that in cells with increased T-SCE, the onset of replicative senescence is dramatically accelerated even though the average rate of telomere loss has not changed. Premature cellular senescence may act as a powerful tumor-suppressor mechanism in telomerase-deficient cells with mutations that cause T-SCE levels to rise. Furthermore, T-SCE-driven premature cellular senescence may be a factor contributing to accelerated aging in Werner and Bloom syndromes, but not XFE progeroid syndrome. PMID:20798040

  2. Age at onset and Parkinson disease phenotype

    PubMed Central

    Pagano, Gennaro; Ferrara, Nicola; Brooks, David J.

    2016-01-01

    Objective: To explore clinical phenotype and characteristics of Parkinson disease (PD) at different ages at onset in recently diagnosed patients with untreated PD. Methods: We have analyzed baseline data from the Parkinson's Progression Markers Initiative database. Four hundred twenty-two patients with a diagnosis of PD confirmed by DaTSCAN imaging were divided into 4 groups according to age at onset (onset younger than 50 years, 50–59 years, 60–69 years, and 70 years or older) and investigated for differences in side, type and localization of symptoms, occurrence/severity of motor and nonmotor features, nigrostriatal function, and CSF biomarkers. Results: Older age at onset was associated with a more severe motor and nonmotor phenotype, a greater dopaminergic dysfunction on DaTSCAN, and reduction of CSF α-synuclein and total tau. The most common presentation was the combination of 2 or 3 motor symptoms (bradykinesia, resting tremor, and rigidity) with rigidity being more common in the young-onset group. In about 80% of the patients with localized onset, the arm was the most affected part of the body, with no difference across subgroups. Conclusions: Although the presentation of PD symptoms is similar across age subgroups, the severity of motor and nonmotor features, the impairment of striatal binding, and the levels of CSF biomarkers increase with age at onset. The variability of imaging and nonimaging biomarkers in patients with PD at different ages could hamper the results of future clinical trials. PMID:26865518

  3. Chronic pancreatitis: Do serum biomarkers provide an association with an inflammageing phenotype?

    PubMed

    Rasch, Sebastian; Valantiene, Irena; Mickevicius, Artautas; Beer, Sebastian; Rosendahl, Jonas; Charnley, Richard M; Robinson, Stuart M

    2016-01-01

    Chronic pancreatitis is an inflammatory disorder of the pancreas that is associated with accelerated mortality for patients suffering from this disease. The association between chronic inflammation and accelerated biological ageing has been well described and is often referred to as "inflammageing". In this review we seek to determine how systemic inflammation in chronic pancreatitis may contribute to an accelerated ageing phenotype. A systematic literature search with a predefined search protocol was performed on Medline, Embase and Cochrane libraries according to the PRISMA guidelines. The initial search identified 499 studies. After title, abstract and full text screen of the search results, 20 were included for further evaluation. In the 20 remaining articles 41 inflammatory mediators were identified - mainly involved in chronic inflammation, fibrosis and particularly cardinal features of inflammageing such as sarcopenia and osteoporosis. Chronic pancreatitis is associated with elevated levels of inflammatory mediators many of which are associated with an accelerated ageing phenotype and may explain some of the clinical sequelae of this disease. Copyright © 2016 IAP and EPC. All rights reserved.

  4. Accelerated DNA Methylation Age: Associations with PTSD and Neural Integrity

    PubMed Central

    Wolf, Erika J.; Logue, Mark W.; Hayes, Jasmeet P.; Sadeh, Naomi; Schichman, Steven A.; Stone, Annjanette; Salat, David H.; Milberg, William; McGlinchey, Regina; Miller, Mark W.

    2015-01-01

    Background Accumulating evidence suggests that post traumatic stress disorder (PTSD) may accelerate cellular aging and lead to premature morbidity and neurocognitive decline. Methods This study evaluated associations between PTSD and DNA methylation (DNAm) age using recently developed algorithms of cellular age by Horvath (2013) and Hannum et al. (2013). These estimates reflect accelerated aging when they exceed chronological age. We also examined if accelerated cellular age manifested in degraded neural integrity, indexed via diffusion tensor imaging. Results Among 281 male and female veterans of the conflicts in Iraq and Afghanistan, DNAm age was strongly related to chronological age (rs ~.88). Lifetime PTSD severity was associated with Hannum DNAm age estimates residualized for chronological age (β = .13, p= .032). Advanced DNAm age was associated with reduced integrity in the genu of the corpus callosum (β = −.17, p= .009) and indirectly linked to poorer working memory performance via this region (indirect β = − .05, p= .029). Horvath DNAm age estimates were not associated with PTSD or neural integrity. Conclusions Results provide novel support for PTSD-related accelerated aging in DNAm and extend the evidence base of known DNAm age correlates to the domains of neural integrity and cognition. PMID:26447678

  5. Perinatally acquired HIV infection accelerates epigenetic aging in South African adolescents.

    PubMed

    Horvath, Steve; Phillips, Nicole; Heany, Sarah J; Kobor, Michael S; Lin, David Ts; Myer, Landon; Zar, Heather J; Stein, Dan J; Levine, Andrew J; Hoare, Jacqueline

    2018-05-08

    Recent studies demonstrate that infection with the Human Immunodeficiency Virus-1 (HIV) is associated with accelerated aging effects in adults according to a highly accurate epigenetic biomarker of aging known as epigenetic clock. However, it not yet known whether epigenetic age acceleration occurs as early as adolescence in perinatally HIV-infected (PHIV+) youth. Observational study of PHIV and HIV-uninfected adolescents enrolled in the Cape Town Adolescent Antiretroviral Cohort (CTAAC) Study. The Illumina EPIC array was used to generate blood DNA methylation data from 204 PHIV and 44 age-matched, uninfected (HIV-) adolescents aged 9 to 12 years old. The epigenetic clock software and method was used to estimate two measures of epigenetic age acceleration. Each participant completed a comprehensive neuropsychological test battery upon enrolment to CTAAC. HIV is associated with biologically older blood in PHIV+ adolescents according to both measures of epigenetic age acceleration. One of the measures, extrinsic epigenetic age acceleration, is negatively correlated with measures of cognitive functioning (executive functioning, working memory, processing speed). Overall, our results indicate that epigenetic age acceleration in blood can be observed in PHIV+ adolescents and that these epigenetic changes accompany poorer cognitive functioning.

  6. Traumatic stress and accelerated DNA methylation age: A meta-analysis.

    PubMed

    Wolf, Erika J; Maniates, Hannah; Nugent, Nicole; Maihofer, Adam X; Armstrong, Don; Ratanatharathorn, Andrew; Ashley-Koch, Allison E; Garrett, Melanie; Kimbrel, Nathan A; Lori, Adriana; Va Mid-Atlantic Mirecc Workgroup; Aiello, Allison E; Baker, Dewleen G; Beckham, Jean C; Boks, Marco P; Galea, Sandro; Geuze, Elbert; Hauser, Michael A; Kessler, Ronald C; Koenen, Karestan C; Miller, Mark W; Ressler, Kerry J; Risbrough, Victoria; Rutten, Bart P F; Stein, Murray B; Ursano, Robert J; Vermetten, Eric; Vinkers, Christiaan H; Uddin, Monica; Smith, Alicia K; Nievergelt, Caroline M; Logue, Mark W

    2018-06-01

    Recent studies examining the association between posttraumatic stress disorder (PTSD) and accelerated aging, as defined by DNA methylation-based estimates of cellular age that exceed chronological age, have yielded mixed results. We conducted a meta-analysis of trauma exposure and PTSD diagnosis and symptom severity in association with accelerated DNA methylation age using data from 9 cohorts contributing to the Psychiatric Genomics Consortium PTSD Epigenetics Workgroup (combined N = 2186). Associations between demographic and cellular variables and accelerated DNA methylation age were also examined, as was the moderating influence of demographic variables. Meta-analysis of regression coefficients from contributing cohorts revealed that childhood trauma exposure (when measured with the Childhood Trauma Questionnaire) and lifetime PTSD severity evidenced significant, albeit small, meta-analytic associations with accelerated DNA methylation age (ps = 0.028 and 0.016, respectively). Sex, CD4T cell proportions, and natural killer cell proportions were also significantly associated with accelerated DNA methylation age (all ps < 0.02). PTSD diagnosis and lifetime trauma exposure were not associated with advanced DNA methylation age. There was no evidence of moderation of the trauma or PTSD variables by demographic factors. Results suggest that traumatic stress is associated with advanced epigenetic age and raise the possibility that cells integral to immune system maintenance and responsivity play a role in this. This study highlights the need for additional research into the biological mechanisms linking traumatic stress to accelerated DNA methylation age and the importance of furthering our understanding of the neurobiological and health consequences of PTSD. Published by Elsevier Ltd.

  7. Challenges of accelerated aging techniques for elastomer lifetime predictions

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gillen, Kenneth T.; Bernstein, R.; Celina, M.

    Elastomers are often degraded when exposed to air or high humidity for extended times (years to decades). Lifetime estimates normally involve extrapolating accelerated aging results made at higher than ambient environments. Several potential problems associated with such studies are reviewed, and experimental and theoretical methods to address them are provided. The importance of verifying time–temperature superposition of degradation data is emphasized as evidence that the overall nature of the degradation process remains unchanged versus acceleration temperature. The confounding effects that occur when diffusion-limited oxidation (DLO) contributes under accelerated conditions are described, and it is shown that the DLO magnitude canmore » be modeled by measurements or estimates of the oxygen permeability coefficient (P Ox) and oxygen consumption rate (Φ). P Ox and Φ measurements can be influenced by DLO, and it is demonstrated how confident values can be derived. In addition, several experimental profiling techniques that screen for DLO effects are discussed. Values of Φ taken from high temperature to temperatures approaching ambient can be used to more confidently extrapolate accelerated aging results for air-aged materials, and many studies now show that Arrhenius extrapolations bend to lower activation energies as aging temperatures are lowered. Furthermore, best approaches for accelerated aging extrapolations of humidity-exposed materials are also offered.« less

  8. Challenges of accelerated aging techniques for elastomer lifetime predictions

    DOE PAGES

    Gillen, Kenneth T.; Bernstein, R.; Celina, M.

    2015-03-01

    Elastomers are often degraded when exposed to air or high humidity for extended times (years to decades). Lifetime estimates normally involve extrapolating accelerated aging results made at higher than ambient environments. Several potential problems associated with such studies are reviewed, and experimental and theoretical methods to address them are provided. The importance of verifying time–temperature superposition of degradation data is emphasized as evidence that the overall nature of the degradation process remains unchanged versus acceleration temperature. The confounding effects that occur when diffusion-limited oxidation (DLO) contributes under accelerated conditions are described, and it is shown that the DLO magnitude canmore » be modeled by measurements or estimates of the oxygen permeability coefficient (P Ox) and oxygen consumption rate (Φ). P Ox and Φ measurements can be influenced by DLO, and it is demonstrated how confident values can be derived. In addition, several experimental profiling techniques that screen for DLO effects are discussed. Values of Φ taken from high temperature to temperatures approaching ambient can be used to more confidently extrapolate accelerated aging results for air-aged materials, and many studies now show that Arrhenius extrapolations bend to lower activation energies as aging temperatures are lowered. Furthermore, best approaches for accelerated aging extrapolations of humidity-exposed materials are also offered.« less

  9. A drug-induced accelerated senescence (DIAS) is a possibility to study aging in time lapse.

    PubMed

    Alili, Lirija; Diekmann, Johanna; Giesen, Melanie; Holtkötter, Olaf; Brenneisen, Peter

    2014-06-01

    Currently, the oxidative stress (or free radical) theory of aging is the most popular explanation of how aging occurs at the molecular level. Accordingly, a stress-induced senescence-like phenotype of human dermal fibroblasts can be induced in vitro by the exposure of human diploid fibroblasts to subcytotoxic concentrations of hydrogen peroxide. However, several biomarkers of replicative senescence e.g. cell cycle arrest and enlarged morphology are abrogated 14 days after treatment, indicating that reactive oxygen species (ROS) rather acts as a trigger for short-term senescence (1-3 days) than being responsible for the maintenance of the senescence-like phenotype. Further, DNA-damaging factors are discussed resulting in a permanent senescent cell type. To induce long-term premature senescence and to understand the molecular alterations occurring during the aging process, we analyzed mitomycin C (MMC) as an alkylating DNA-damaging agent and ROS producer. Human dermal fibroblasts (HDF), used as model for skin aging, were exposed to non-cytotoxic concentrations of MMC and analyzed for potential markers of cellular aging, for example enlarged morphology, activity of senescence-associated-ß-galactosidase, cell cycle arrest, increased ROS production and MMP1-activity, which are well-documented for HDF in replicative senescence. Our data show that mitomycin C treatment results in a drug-induced accelerated senescence (DIAS) with long-term expression of senescence markers, demonstrating that a combination of different susceptibility factors, here ROS and DNA alkylation, are necessary to induce a permanent senescent cell type.

  10. Bio-Spectroscopic Imaging Provides Evidence of Hippocampal Zn Deficiency and Decreased Lipid Unsaturation in an Accelerated Ageing Mouse Model.

    PubMed

    Fimognari, Nicholas; Hollings, Ashley; Lam, Virginie; Tidy, Rebecca J; Kewish, Cameron M; Albrecht, Matthew A; Takechi, Ryu; Mamo, John C L; Hackett, Mark J

    2018-06-14

    Western society is facing a health epidemic due to the increasing incidence of dementia in ageing populations, and there are still few effective diagnostic methods, minimal treatment options, and no cure. Ageing is the greatest risk factor for memory loss that occurs during the natural ageing process, as well as being the greatest risk factor for neurodegenerative disease such as Alzheimer's disease. Therefore, greater understanding of the biochemical pathways that drive a healthy ageing brain towards dementia (pathological ageing or Alzheimer's disease), is required to accelerate the development of improved diagnostics and therapies. Unfortunately, many animal models of dementia model chronic amyloid precursor protein over-expression, which although highly relevant to mechanisms of amyloidosis and familial Alzheimer's disease, does not model well dementia during the natural ageing process. A promising animal model reported to model mechanisms of accelerated natural ageing and memory impairments, is the senescence accelerated murine prone strain 8 (SAMP8), which has been adopted by many research group to study the biochemical transitions that occur during brain ageing. A limitation to traditional methods of biochemical characterisation is that many important biochemical and elemental markers (lipid saturation, lactate, transition metals) cannot be imaged at meso- or micro-spatial resolution. Therefore, in this investigation we report the first multi-modal biospectroscopic characterisation of the SAMP8 model, and have identified important biochemical and elemental alterations, and co-localisations, between 4 month old SAMP8 mice and the relevant control (SAMR1) mice. Specifically, we demonstrate direct evidence of altered metabolism and disturbed lipid homeostasis within corpus callosum white matter, in addition to localised hippocampal metal deficiencies, in the accelerated ageing phenotype. Such findings have important implication for future research aimed at

  11. Microglial aging in the healthy CNS: phenotypes, drivers, and rejuvenation

    PubMed Central

    Wong, Wai T.

    2013-01-01

    Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and age-related macular degeneration (AMD), share two characteristics in common: (1) a disease prevalence that increases markedly with advancing age, and (2) neuroinflammatory changes in which microglia, the primary resident immune cell of the CNS, feature prominently. These characteristics have led to the hypothesis that pathogenic mechanisms underlying age-related neurodegenerative disease involve aging changes in microglia. If correct, targeting features of microglial senescence may constitute a feasible therapeutic strategy. This review explores this hypothesis and its implications by considering the current knowledge on how microglia undergo change during aging and how the emergence of these aging phenotypes relate to significant alterations in microglial function. Evidence and theories on cellular mechanisms implicated in driving senescence in microglia are reviewed, as are “rejuvenative” measures and strategies that aim to reverse or ameliorate the aging microglial phenotype. Understanding and controlling microglial aging may represent an opportunity for elucidating disease mechanisms and for formulating novel therapies. PMID:23493481

  12. Accelerated epigenetic aging in Down syndrome

    PubMed Central

    Horvath, Steve; Garagnani, Paolo; Bacalini, Maria Giulia; Pirazzini, Chiara; Salvioli, Stefano; Gentilini, Davide; Di Blasio, Anna Maria; Giuliani, Cristina; Tung, Spencer; Vinters, Harry V; Franceschi, Claudio

    2015-01-01

    Down Syndrome (DS) entails an increased risk of many chronic diseases that are typically associated with older age. The clinical manifestations of accelerated aging suggest that trisomy 21 increases the biological age of tissues, but molecular evidence for this hypothesis has been sparse. Here, we utilize a quantitative molecular marker of aging (known as the epigenetic clock) to demonstrate that trisomy 21 significantly increases the age of blood and brain tissue (on average by 6.6 years, P = 7.0 × 10−14). PMID:25678027

  13. BrainAGE score indicates accelerated brain aging in schizophrenia, but not bipolar disorder.

    PubMed

    Nenadić, Igor; Dietzek, Maren; Langbein, Kerstin; Sauer, Heinrich; Gaser, Christian

    2017-08-30

    BrainAGE (brain age gap estimation) is a novel morphometric parameter providing a univariate score derived from multivariate voxel-wise analyses. It uses a machine learning approach and can be used to analyse deviation from physiological developmental or aging-related trajectories. Using structural MRI data and BrainAGE quantification of acceleration or deceleration of in individual aging, we analysed data from 45 schizophrenia patients, 22 bipolar I disorder patients (mostly with previous psychotic symptoms / episodes), and 70 healthy controls. We found significantly higher BrainAGE scores in schizophrenia, but not bipolar disorder patients. Our findings indicate significantly accelerated brain structural aging in schizophrenia. This suggests, that despite the conceptualisation of schizophrenia as a neurodevelopmental disorder, there might be an additional progressive pathogenic component. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  14. Accelerated aging: prediction of chemical stability of pharmaceuticals.

    PubMed

    Waterman, Kenneth C; Adami, Roger C

    2005-04-11

    Methods of rapidly and accurately assessing the chemical stability of pharmaceutical dosage forms are reviewed with respect to the major degradation mechanisms generally observed in pharmaceutical development. Methods are discussed, with the appropriate caveats, for accelerated aging of liquid and solid dosage forms, including small and large molecule active pharmaceutical ingredients. In particular, this review covers general thermal methods, as well as accelerated aging methods appropriate to oxidation, hydrolysis, reaction with reactive excipient impurities, photolysis and protein denaturation.

  15. Accelerated Aging with Electrical Overstress and Prognostics for Power MOSFETs

    NASA Technical Reports Server (NTRS)

    Saha, Sankalita; Celaya, Jose Ramon; Vashchenko, Vladislav; Mahiuddin, Shompa; Goebel, Kai F.

    2011-01-01

    Power electronics play an increasingly important role in energy applications as part of their power converter circuits. Understanding the behavior of these devices, especially their failure modes as they age with nominal usage or sudden fault development is critical in ensuring efficiency. In this paper, a prognostics based health management of power MOSFETs undergoing accelerated aging through electrical overstress at the gate area is presented. Details of the accelerated aging methodology, modeling of the degradation process of the device and prognostics algorithm for prediction of the future state of health of the device are presented. Experiments with multiple devices demonstrate the performance of the model and the prognostics algorithm as well as the scope of application. Index Terms Power MOSFET, accelerated aging, prognostics

  16. Suspected ontogeny of a recently described hypo-androgenic PCOS-like phenotype with advancing age.

    PubMed

    Gleicher, Norbert; Kushnir, Vitaly A; Darmon, Sarah K; Wang, Qi; Zhang, Lin; Albertini, David F; Barad, David H

    2018-03-01

    A recent report described a new PCOS-like phenotype in lean older infertile women, and was characterized by high age-specific anti-Müllerian hormone (AMH) but hypo- rather than the expected hyper-androgenism. The hypo-androgenism was, furthermore, characterized of, likely, adrenal origin and autoimmune etiology. We extracted data on 708 consecutive infertility patients, and separated them into three age-strata, <35, 36-42, and >42 years. In each stratum, we investigated how levels of anti-Müllerian hormone (AMH) and testosterone (T) interrelate between high-AMH (AMH ≥ 75th quantile) and normal AMH (25th-75th quantile) and low-T (total testosterone ≤19.0 ng/dL), normal-T (19.0-29.0 ng/dL) and high-T (>29.0 ng/dL). High-AMH cycles were presumed to reflect PCOS-like patients. Routine in vitro fertilization (IVF) cycle outcomes and clinical phenotypes of patients were then compared between groups with AMH and T as statistical variables. This hypo-androgenic PCOS-like phenotype already exists in age stratum <35 years. It appears to arise from a lean, at very young ages hyper-androgenic PCOS phenotype that develops in comparison to controls (likely autoimmune-induced) insufficiency of the adrenal zona reticularis (low-T and low-DHEAS) and zona fasciculata (low-C), and is characterized by frequent evidence of autoimmunity. A degree of adrenal insufficiency, thus, concomitantly appears to affect adrenal androgen and, to lesser degrees, glucocorticoid production (mineralocorticoids were not investigated). Here investigated new PCOS-like phenotype demonstrates features compatible with what under Rotterdam criteria has been referred to as PCOS phenotype-D. If confirmed, the observation that the ontogeny of this phenotype already at young ages is, likely, driven by adrenal autoimmunity, supports the position of the androgen excess and PCOS society that the etiology of phenotype-D differs from that of classical hyper-androgenic PCOS of mostly ovarian etiology.

  17. Life stress, glucocorticoid signaling, and the aging epigenome: Implications for aging-related diseases.

    PubMed

    Gassen, Nils C; Chrousos, George P; Binder, Elisabeth B; Zannas, Anthony S

    2017-03-01

    Life stress has been associated with accelerated cellular aging and increased risk for developing aging-related diseases; however, the underlying molecular mechanisms remain elusive. A highly relevant process that may underlie this association is epigenetic regulation. In this review, we build upon existing evidence to propose a model whereby exposure to life stress, in part via its effects on the hypothalamic-pituitary axis and the glucocorticoid signaling system, may alter the epigenetic landscape across the lifespan and, consequently, influence genomic regulation and function in ways that are conducive to the development of aging-related diseases. This model is supported by recent studies showing that life stressors and stress-related phenotypes can accelerate epigenetic aging, a measure that is based on DNA methylation prediction of chronological age and has been associated with several aging-related disease phenotypes. We discuss the implications of this model for the prevention and treatment of aging-related diseases, as well as the challenges and limitations of this line of research. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Is biological aging accelerated in drug addiction?

    PubMed

    Bachi, Keren; Sierra, Salvador; Volkow, Nora D; Goldstein, Rita Z; Alia-Klein, Nelly

    2017-02-01

    Drug-addiction may trigger early onset of age-related disease, due to drug-induced multi-system toxicity and perilous lifestyle, which remains mostly undetected and untreated. We present the literature on pathophysiological processes that may hasten aging and its relevance to addiction, including: oxidative stress and cellular aging, inflammation in periphery and brain, decline in brain volume and function, and early onset of cardiac, cerebrovascular, kidney, and liver disease. Timely detection of accelerated aging in addiction is crucial for the prevention of premature morbidity and mortality.

  19. Huntington's Disease: Relationship Between Phenotype and Genotype.

    PubMed

    Sun, Yi-Min; Zhang, Yan-Bin; Wu, Zhi-Ying

    2017-01-01

    Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disease with the typical manifestations of involuntary movements, psychiatric and behavior disorders, and cognitive impairment. It is caused by the dynamic mutation in CAG triplet repeat number in exon 1 of huntingtin (HTT) gene. The symptoms of HD especially the age at onset are related to the genetic characteristics, both the CAG triplet repeat and the modified factors. Here, we reviewed the recent advancement on the genotype-phenotype relationship of HD, mainly focus on the characteristics of different expanded CAG repeat number, genetic modifiers, and CCG repeat number in the 3' end of CAG triplet repeat and their effects on the phenotype. We also reviewed the special forms of HD (juvenile HD, atypical onset HD, and homozygous HD) and their phenotype-genotype correlations. The review will aid clinicians to predict the onset age and disease course of HD, give the genetic counseling, and accelerate research into the HD mechanism.

  20. Accelerated aging, natural aging, and small punch testing of gamma-air sterilized polycarbonate urethane acetabular components.

    PubMed

    Kurtz, S M; Siskey, R; Reitman, M

    2010-05-01

    The objectives of this study were three-fold: (1) to determine the applicability of the small punch test to characterize Bionate 80A polycarbonate urethane (PCU) acetabular implants; (2) to evaluate the susceptibility of PCU acetabular implants to exhibit degradation of mechanical behavior following gamma irradiation in air and accelerated aging; and (3) to compare the oxidation of gamma-air sterilized PCU following accelerated aging and 5 years of natural shelf aging. In addition to attenuated total reflectance-Fourier transform infrared spectroscopy, we also adapted a miniature specimen mechanical test, the small punch test, for the deformable PCU cups. Accelerated aging was performed using ASTM F2003, a standard test that represents a severe oxidative challenge. The results of this study suggest that the small punch test is sufficiently sensitive and reproducible to discriminate slight differences in the large-deformation mechanical behavior of Bionate 80A following accelerated aging. The gamma-air sterilized PCU had a reduction of 9% in ultimate load after aging. Five years of shelf aging had little effect on the mechanical properties of the PCU. Overall, our findings suggest that the Bionate 80A material has greater oxidative stability than ultra-high molecular weight polyethylene following gamma irradiation in air and exposure to a severe oxidative challenge. (c) 2010 Wiley Periodicals, Inc.

  1. Are Anxiety Disorders Associated with Accelerated Aging? A Focus on Neuroprogression

    PubMed Central

    Perna, Giampaolo; Iannone, Giuseppe; Alciati, Alessandra; Caldirola, Daniela

    2016-01-01

    Anxiety disorders (AnxDs) are highly prevalent throughout the lifespan, with detrimental effects on daily-life functioning, somatic health, and quality of life. An emerging perspective suggested that AnxDs may be associated with accelerated aging. In this paper, we explored the association between AnxDs and hallmarks of accelerated aging, with a specific focus on neuroprogression. We reviewed animal and human findings that suggest an overlap between processes of impaired neurogenesis, neurodegeneration, structural, functional, molecular, and cellular modifications in AnxDs, and aging. Although this research is at an early stage, our review suggests a link between anxiety and accelerated aging across multiple processes involved in neuroprogression. Brain structural and functional changes that accompany normal aging were more pronounced in subjects with AnxDs than in coevals without AnxDs, including reduced grey matter density, white matter alterations, impaired functional connectivity of large-scale brain networks, and poorer cognitive performance. Similarly, molecular correlates of brain aging, including telomere shortening, Aβ accumulation, and immune-inflammatory and oxidative/nitrosative stress, were overrepresented in anxious subjects. No conclusions about causality or directionality between anxiety and accelerated aging can be drawn. Potential mechanisms of this association, limitations of the current research, and implications for treatments and future studies are discussed. PMID:26881136

  2. Accelerated aging of concrete : a literature review

    DOT National Transportation Integrated Search

    2002-02-01

    This report provides a review of the literature on accelerated aging of concrete. It was undertaken, as part of a research project : on predicting the long-term environmental performance of Portland cement concrete (PCC) pavements containing coal fly...

  3. Reversible Age-Related Phenotypes Induced during Larval Quiescence in C. elegans

    PubMed Central

    Roux, Antoine E.; Langhans, Kelley; Huynh, Walter; Kenyon, Cynthia

    2017-01-01

    Summary Cells can enter quiescent states in which cell cycling and growth are suspended. We find that during a long developmental arrest (quiescence) induced by starvation, newly-hatched C. elegans acquire features associated with impaired proteostasis and aging: mitochondrial fission, ROS production, protein aggregation, decreased proteotoxic-stress resistance, and at the organismal level, decline of mobility and high mortality. All signs of aging but one, the presence of protein aggregates, were reversed upon return to development induced by feeding. The endoplasmic reticulum receptor IRE-1 is completely required for recovery, and the downstream transcription factor XBP-1, as well as a protein kinase, KGB-1, are partially required. Interestingly, kgb-1(−) mutants that do recover fail to reverse aging-like mitochondrial phenotypes and have a short adult lifespan. Our study describes the first pathway that reverses phenotypes of aging at the exit of prolonged quiescence. PMID:27304510

  4. Accelerated aging of phenolic-bonded flakeboards

    Treesearch

    Andrew J. Baker; Robert H. Gillespie

    1978-01-01

    Specimens of phenolic-bonded flakeboard, vertical-grain southern pine and Douglas-fir, and marine-grade Douglas-fir plywood were exposed to four accelerated aging situations. These consisted of: 1) Multiple cycles of boiling and elevated-temperature drying, 2) multiple cycles of vacuum- pressure soaking and intermediate-temperature drying, 3) the six-cycle ASTM D-1037...

  5. [The use of biological age on mental work capacity model in accelerated aging assessment of professional lorry-drivers].

    PubMed

    Bashkireva, A S

    2012-01-01

    The studies of biological age, aging rate, mental work capacity in professional drivers were conducted. The examination revealed peculiarities of system organization of functions determining the mental work capacity levels. Dynamics of the aging process of professional driver's organism in relation with calendar age and driving experience were shown using the biological age model. The results point at the premature decrease of the mental work capacity in professional drivers. It was proved, that premature age-related changes of physiologic and psychophysiologic indices in drivers are just "risk indicators", while long driving experience is a real risk factor, accelerating the aging process. The "risk group" with manifestations of accelerating aging was observed in 40-49-year old drivers with 15-19 years of professional experience. The expediency of using the following methods for the age rate estimation according to biologic age indices and necessity of prophylactic measures for premature and accelerated aging prevention among working population was demonstrated.

  6. Aging Microglia—Phenotypes, Functions and Implications for Age-Related Neurodegenerative Diseases

    PubMed Central

    Spittau, Björn

    2017-01-01

    Aging of the central nervous system (CNS) is one of the major risk factors for the development of neurodegenerative pathologies such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). The molecular mechanisms underlying the onset of AD and especially PD are not well understood. However, neuroinflammatory responses mediated by microglia as the resident immune cells of the CNS have been reported for both diseases. The unique nature and developmental origin of microglia causing microglial self-renewal and telomere shortening led to the hypothesis that these CNS-specific innate immune cells become senescent. Age-dependent and senescence-driven impairments of microglia functions and responses have been suggested to play essential roles during onset and progression of neurodegenerative diseases. This review article summarizes the current knowledge of microglia phenotypes and functions in the aging CNS and further discusses the implications of these age-dependent microglia changes for the development and progression of AD and PD as the most common neurodegenerative diseases. PMID:28659790

  7. HIV-associated cellular senescence: A contributor to accelerated aging.

    PubMed

    Cohen, Justin; Torres, Claudio

    2017-07-01

    Due to the advent of antiretroviral therapy HIV is no longer a terminal disease and the HIV infected patients are becoming increasingly older. While this is a major success, with increasing age comes an increased risk for disease. The age-related comorbidities that HIV infected patients experience suggest that they suffer from accelerated aging. One possible contributor to this accelerated aging is cellular senescence, an age-associated response that can occur prematurely in response to stress, and that is emerging as a contributor to disease and aging. HIV patients experience several stressors such as the virus itself, antiretroviral drugs and to a lesser extent, substance abuse that can induce cellular senescence. This review summarizes the current knowledge of senescence induction in response to these stressors and their relation to the comorbidities in HIV patients. Cellular senescence may be a possible therapeutic target for these comorbidities. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Accelerated Brain Aging in Schizophrenia: A Longitudinal Pattern Recognition Study.

    PubMed

    Schnack, Hugo G; van Haren, Neeltje E M; Nieuwenhuis, Mireille; Hulshoff Pol, Hilleke E; Cahn, Wiepke; Kahn, René S

    2016-06-01

    Despite the multitude of longitudinal neuroimaging studies that have been published, a basic question on the progressive brain loss in schizophrenia remains unaddressed: Does it reflect accelerated aging of the brain, or is it caused by a fundamentally different process? The authors used support vector regression, a supervised machine learning technique, to address this question. In a longitudinal sample of 341 schizophrenia patients and 386 healthy subjects with one or more structural MRI scans (1,197 in total), machine learning algorithms were used to build models to predict the age of the brain and the presence of schizophrenia ("schizophrenia score"), based on the gray matter density maps. Age at baseline ranged from 16 to 67 years, and follow-up scans were acquired between 1 and 13 years after the baseline scan. Differences between brain age and chronological age ("brain age gap") and between schizophrenia score and healthy reference score ("schizophrenia gap") were calculated. Accelerated brain aging was calculated from changes in brain age gap between two consecutive measurements. The age prediction model was validated in an independent sample. In schizophrenia patients, brain age was significantly greater than chronological age at baseline (+3.36 years) and progressively increased during follow-up (+1.24 years in addition to the baseline gap). The acceleration of brain aging was not constant: it decreased from 2.5 years/year just after illness onset to about the normal rate (1 year/year) approximately 5 years after illness onset. The schizophrenia gap also increased during follow-up, but more pronounced variability in brain abnormalities at follow-up rendered this increase nonsignificant. The progressive brain loss in schizophrenia appears to reflect two different processes: one relatively homogeneous, reflecting accelerated aging of the brain and related to various measures of outcome, and a more variable one, possibly reflecting individual variation and

  9. Protocols and programs for high-throughput growth and aging phenotyping in yeast.

    PubMed

    Jung, Paul P; Christian, Nils; Kay, Daniel P; Skupin, Alexander; Linster, Carole L

    2015-01-01

    In microorganisms, and more particularly in yeasts, a standard phenotyping approach consists in the analysis of fitness by growth rate determination in different conditions. One growth assay that combines high throughput with high resolution involves the generation of growth curves from 96-well plate microcultivations in thermostated and shaking plate readers. To push the throughput of this method to the next level, we have adapted it in this study to the use of 384-well plates. The values of the extracted growth parameters (lag time, doubling time and yield of biomass) correlated well between experiments carried out in 384-well plates as compared to 96-well plates or batch cultures, validating the higher-throughput approach for phenotypic screens. The method is not restricted to the use of the budding yeast Saccharomyces cerevisiae, as shown by consistent results for other species selected from the Hemiascomycete class. Furthermore, we used the 384-well plate microcultivations to develop and validate a higher-throughput assay for yeast Chronological Life Span (CLS), a parameter that is still commonly determined by a cumbersome method based on counting "Colony Forming Units". To accelerate analysis of the large datasets generated by the described growth and aging assays, we developed the freely available software tools GATHODE and CATHODE. These tools allow for semi-automatic determination of growth parameters and CLS behavior from typical plate reader output files. The described protocols and programs will increase the time- and cost-efficiency of a number of yeast-based systems genetics experiments as well as various types of screens.

  10. Phenotypes of sleep-disordered breathing symptoms to two years of age based on age of onset and duration of symptoms.

    PubMed

    Kamal, Muna; Tamana, Sukhpreet K; Smithson, Lisa; Ding, Linda; Lau, Amanda; Chikuma, Joyce; Mariasine, Jennifer; Lefebvre, Diana L; Subbarao, Padmaja; Becker, Allan B; Turvey, Stuart E; Sears, Malcolm R; Pei, Jacqueline; Mandhane, Piush J

    2018-05-03

    Childhood sleep-disordered breathing (SDB) symptoms may comprise multiple phenotypes depending on craniofacial anatomy, tonsil and adenoid growth, body habitus, and rhinitis symptoms. The primary objective of this study is to identify and characterize the different SDB phenotypes to two years of age. Data from 770 infants in the Edmonton sub-cohort of the Canadian Healthy Infant Longitudinal Study (CHILD) were analyzed to identify SDB phenotypes based on age of onset and duration of symptoms. Parents completed the 22-item sleep-related breathing disorder (SRBD) scale. Children with a SRBD ratio greater than 0.33 were considered positive for SDB at each quarterly assessment between three months and two years. The STATA Proc trajectory extension identified SDB phenotypes based on their age of onset and duration of symptoms and attributed the percentage chance of a participant being assigned to each phenotype. Multivariate linear regression identified factors associated with increased risk of being assigned to each SDB phenotype. Trajectory analysis identified four phenotypes: no SDB (65.7%), early-onset SDB (15.7%) with peak symptoms at nine months, late-onset SDB (14.2%) with peak symptoms at 18 months, and persistent SDB (5.3%) with symptoms from 3 to 24 months. Rhinitis was associated with all three SDB symptom trajectories (p < 0.05). Children with gastroesophageal reflux disease presented with early (p = 0.03) and late SDB (p < 0.001). Maternal obstructive sleep apnea syndrome (OSAS) was associated with persistent (p = 0.01) and late SDB (p < 0.001). Atopy (positive skin prick test at one year) was associated with persistent SDB (p = 0.04). Infants born prior to 36.5 weeks gestational age were more likely to present with late SDB (p = 0.03). Childhood SDB symptoms, rather than being a homogenous disorder, may comprise multiple overlapping phenotypes each with unique risk factors. Copyright © 2018 Elsevier B.V. All rights reserved.

  11. Age-related increase in Wnt inhibitor causes a senescence-like phenotype in human cardiac stem cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Nakamura, Tamami; Hosoyama, Tohru; Regenerative Medicine Institute, Yamaguchi University Graduate School of Medicine

    Aging of cardiac stem/progenitor cells (CSCs) impairs heart regeneration and leads to unsatisfactory outcomes of cell-based therapies. As the precise mechanisms underlying CSC aging remain unclear, the use of therapeutic strategies for elderly patients with heart failure is severely delayed. In this study, we used human cardiosphere-derived cells (CDCs), a subtype of CSC found in the postnatal heart, to identify secreted factor(s) associated with CSC aging. Human CDCs were isolated from heart failure patients of various ages (2–83 years old). Gene expression of key soluble factors was compared between CDCs derived from young and elderly patients. Among these factors, SFRP1,more » a gene encoding a Wnt antagonist, was significantly up-regulated in CDCs from elderly patients (≥65 years old). sFRP1 levels was increased significantly also in CDCs, whose senescent phenotype was induced by anti-cancer drug treatment. These results suggest the participation of sFRP1 in CSC aging. We show that the administration of recombinant sFRP1 induced cellular senescence in CDCs derived from young patients, as indicated by increased levels of markers such as p16, and a senescence-associated secretory phenotype. In addition, co-administration of recombinant sFRP1 could abrogate the accelerated CDC proliferation induced by Wnt3A. Taken together, our results suggest that canonical Wnt signaling and its antagonist, sFRP1, regulate proliferation of human CSCs. Furthermore, excess sFRP1 in elderly patients causes CSC aging. - Highlights: • Wnt signaling regulates proliferation of human cardiac stem cells. • Expression of sFRP1, which is a Wnt antagonist, is up-regulated in elderly patients with heart failure. • Expression of sFRP1 is increased in anti-cancer drug-induced senescent human cardiac stem cells. • sFRP1 causes cellular senescence of young patients-derived cardiac stem cells.« less

  12. Calpain 1 inhibitor BDA-410 ameliorates α-klotho-deficiency phenotypes resembling human aging-related syndromes.

    PubMed

    Nabeshima, Yoko; Washida, Miwa; Tamura, Masaru; Maeno, Akiteru; Ohnishi, Mutsuko; Shiroishi, Toshihiko; Imura, Akihiro; Razzaque, M Shawkat; Nabeshima, Yo-ichi

    2014-08-01

    Taking good care of elderly is a major challenge of our society, and thus identification of potential drug targets to reduce age-associated disease burden is desirable. α-klotho(-/-) (α-kl) is a short-lived mouse model that displays multiple phenotypes resembling human aging-related syndromes. Such ageing phenotype of α-kl(-/-) mice is associated with activation of a proteolytic enzyme, Calpain-1. We hypothesized that uncontrolled activation of calpain-1 might be causing age-related phenotypes in α-kl-deficient mice. We found that daily administration of BDA-410, a calpain-1 inhibitor, strikingly ameliorated multiple aging-related phenotypes. Treated mice showed recovery of reproductive ability, increased body weight, reduced organ atrophy, and suppression of ectopic calcifications, bone mineral density reduction, pulmonary emphysema and senile atrophy of skin. We also observed ectopic expression of FGF23 in calcified arteries of α-kl(-/-) mice, which might account for the clinically observed association of increased FGF23 level with increased risk of cardiovascular mortality. These findings allow us to propose that modulation of calpain-1 activity is a potential therapeutic option for delaying age-associated organ pathology, particularly caused by the dysregulation of mineral ion homeostasis.

  13. Calpain 1 inhibitor BDA-410 ameliorates α-klotho-deficiency phenotypes resembling human aging-related syndromes

    PubMed Central

    Nabeshima, Yoko; Washida, Miwa; Tamura, Masaru; Maeno, Akiteru; Ohnishi, Mutsuko; Shiroishi, Toshihiko; Imura, Akihiro; Razzaque, M. Shawkat; Nabeshima, Yo-ichi

    2014-01-01

    Taking good care of elderly is a major challenge of our society, and thus identification of potential drug targets to reduce age-associated disease burden is desirable. α-klotho-/- (α-kl) is a short-lived mouse model that displays multiple phenotypes resembling human aging-related syndromes. Such ageing phenotype of α-kl-/- mice is associated with activation of a proteolytic enzyme, Calpain-1. We hypothesized that uncontrolled activation of calpain-1 might be causing age-related phenotypes in α-kl-deficient mice. We found that daily administration of BDA-410, a calpain-1 inhibitor, strikingly ameliorated multiple aging-related phenotypes. Treated mice showed recovery of reproductive ability, increased body weight, reduced organ atrophy, and suppression of ectopic calcifications, bone mineral density reduction, pulmonary emphysema and senile atrophy of skin. We also observed ectopic expression of FGF23 in calcified arteries of α-kl-/- mice, which might account for the clinically observed association of increased FGF23 level with increased risk of cardiovascular mortality. These findings allow us to propose that modulation of calpain-1 activity is a potential therapeutic option for delaying age-associated organ pathology, particularly caused by the dysregulation of mineral ion homeostasis. PMID:25080854

  14. Multicenter Evaluation of the Accelerate PhenoTest BC Kit for Rapid Identification and Phenotypic Antimicrobial Susceptibility Testing Using Morphokinetic Cellular Analysis

    PubMed Central

    2018-01-01

    ABSTRACT We describe results from a multicenter study evaluating the Accelerate Pheno system, a first of its kind diagnostic system that rapidly identifies common bloodstream pathogens from positive blood cultures within 90 min and determines bacterial phenotypic antimicrobial susceptibility testing (AST) results within ∼7 h. A combination of fresh clinical and seeded blood cultures were tested, and results from the Accelerate Pheno system were compared to Vitek 2 results for identification (ID) and broth microdilution or disk diffusion for AST. The Accelerate Pheno system accurately identified 14 common bacterial pathogens and two Candida spp. with sensitivities ranging from 94.6 to 100%. Of fresh positive blood cultures, 89% received a monomicrobial call with a positive predictive value of 97.3%. Six common Gram-positive cocci were evaluated for ID. Five were tested against eight antibiotics, two resistance phenotypes (methicillin-resistant Staphylococcus aureus and Staphylococcus spp. [MRSA/MRS]), and inducible clindamycin resistance (MLSb). From the 4,142 AST results, the overall essential agreement (EA) and categorical agreement (CA) were 97.6% and 97.9%, respectively. Overall very major error (VME), major error (ME), and minor error (mE) rates were 1.0%, 0.7%, and 1.3%, respectively. Eight species of Gram-negative rods were evaluated against 15 antibiotics. From the 6,331 AST results, overall EA and CA were 95.4% and 94.3%, respectively. Overall VME, ME, and mE rates were 0.5%, 0.9%, and 4.8%, respectively. The Accelerate Pheno system has the unique ability to identify and provide phenotypic MIC and categorical AST results in a few hours directly from positive blood culture bottles and support accurate antimicrobial adjustment. PMID:29305546

  15. Accelerated Aging in Electrolytic Capacitors for Prognostics

    NASA Technical Reports Server (NTRS)

    Celaya, Jose R.; Kulkarni, Chetan; Saha, Sankalita; Biswas, Gautam; Goebel, Kai Frank

    2012-01-01

    The focus of this work is the analysis of different degradation phenomena based on thermal overstress and electrical overstress accelerated aging systems and the use of accelerated aging techniques for prognostics algorithm development. Results on thermal overstress and electrical overstress experiments are presented. In addition, preliminary results toward the development of physics-based degradation models are presented focusing on the electrolyte evaporation failure mechanism. An empirical degradation model based on percentage capacitance loss under electrical overstress is presented and used in: (i) a Bayesian-based implementation of model-based prognostics using a discrete Kalman filter for health state estimation, and (ii) a dynamic system representation of the degradation model for forecasting and remaining useful life (RUL) estimation. A leave-one-out validation methodology is used to assess the validity of the methodology under the small sample size constrain. The results observed on the RUL estimation are consistent through the validation tests comparing relative accuracy and prediction error. It has been observed that the inaccuracy of the model to represent the change in degradation behavior observed at the end of the test data is consistent throughout the validation tests, indicating the need of a more detailed degradation model or the use of an algorithm that could estimate model parameters on-line. Based on the observed degradation process under different stress intensity with rest periods, the need for more sophisticated degradation models is further supported. The current degradation model does not represent the capacitance recovery over rest periods following an accelerated aging stress period.

  16. Accelerated Aging of Lead-Free Propellant

    NASA Technical Reports Server (NTRS)

    Furrow, Keith W.; Jervey, David D.

    2000-01-01

    Following higher than expected 2-NDPA depletion rates in a lead-free doublebase formulation (RPD-422), an accelerated aging study was conducted to verify the depletion rates. A test plan was prepared to compare the aging characteristics of lead-free propellant and NOSIH-AA2. The study was also designed to determine which lead-free ballistic modifiers accelerated 2-NDPA depletion. The increased depletion rate occurred in propellants containing monobasic copper salicylate. Four lead-free propellants were then formulated to improved aging characteristics over previous lead-free propellant formulations. The new formulations reduced or replaced the monobasic copper salicylate. The new formulations had improved aging characteristics. Their burn rates, however, were unacceptable for use in a 2.75 inch rocket. To compare aging characteristics, stabilizer depletion rates of RPD-422, AA2, M28, and RLC 470/6A were measured or taken from the literature. The data were fit to a kinetic model. The model contained first and zero order terms which allowed the stabilizer concentration to go to zero. In the model, only the concentration of the primary stabilizer was considered. Derivatives beyond the first nitrated or nitroso derivative of 2-NPDA were not considered. The rate constants were fit to the Arrhenius equation and extrapolated to lower temperatures. The time to complete stabilizer depletion was estimated using the kinetic model. The four propellants were compared and the RPD-422 depleted faster at 45 C than both A22 and M28. These types of predictions depend on the validity of the model and on confidence in the Arrhenius relationship holding at lower temperatures. At 45 C, the zero order portion of the model dominates the depletion rate.

  17. Spotted phenotypes in horses lost attractiveness in the Middle Ages

    PubMed Central

    Wutke, Saskia; Benecke, Norbert; Sandoval-Castellanos, Edson; Döhle, Hans-Jürgen; Friederich, Susanne; Gonzalez, Javier; Hallsson, Jón Hallsteinn; Hofreiter, Michael; Lõugas, Lembi; Magnell, Ola; Morales-Muniz, Arturo; Orlando, Ludovic; Pálsdóttir, Albína Hulda; Reissmann, Monika; Ruttkay, Matej; Trinks, Alexandra; Ludwig, Arne

    2016-01-01

    Horses have been valued for their diversity of coat colour since prehistoric times; this is especially the case since their domestication in the Caspian steppe in ~3,500 BC. Although we can assume that human preferences were not constant, we have only anecdotal information about how domestic horses were influenced by humans. Our results from genotype analyses show a significant increase in spotted coats in early domestic horses (Copper Age to Iron Age). In contrast, medieval horses carried significantly fewer alleles for these phenotypes, whereas solid phenotypes (i.e., chestnut) became dominant. This shift may have been supported because of (i) pleiotropic disadvantages, (ii) a reduced need to separate domestic horses from their wild counterparts, (iii) a lower religious prestige, or (iv) novel developments in weaponry. These scenarios may have acted alone or in combination. However, the dominance of chestnut is a remarkable feature of the medieval horse population. PMID:27924839

  18. Age-dependent phenotypic characteristics of a triple transgenic mouse model of Alzheimer disease.

    PubMed

    Pietropaolo, Susanna; Feldon, Joram; Yee, Benjamin K

    2008-08-01

    The triple-transgenic mouse line (3 x Tg-AD) harboring PS1M146V, APPSwe, and taup301L transgenes represents the only transgenic model for Alzheimer's disease (AD) to date capturing both beta-amyloid and tau neuropathology. The present study provides an extensive behavioral characterization of the 3 x Tg-AD mouse line, evaluating the emergence of noncognitive and cognitive AD-like symptoms at two ages corresponding to the early (6-7 months) and advanced (12-13 months) stages of AD-pathology. Enhanced responsiveness to aversive stimulation was detected in mutant mice at both ages: the 3 x Tg-AD genotype enhanced acoustic startle response and facilitated performance in the cued-version of the water maze. These noncognitive phenotypes were accompanied by hyperactivity and reduced locomotor habituation in the open field at the older age. Signs of cognitive aberrations were also detected at both ages, but they were limited to associative learning. The present study suggests that this popular transgenic mouse model of AD has clear phenotypes beyond the cognitive domain, and their potential relationship to the cognitive phenotypes should be further explored.

  19. Huntington's disease accelerates epigenetic aging of human brain and disrupts DNA methylation levels.

    PubMed

    Horvath, Steve; Langfelder, Peter; Kwak, Seung; Aaronson, Jeff; Rosinski, Jim; Vogt, Thomas F; Eszes, Marika; Faull, Richard L M; Curtis, Maurice A; Waldvogel, Henry J; Choi, Oi-Wa; Tung, Spencer; Vinters, Harry V; Coppola, Giovanni; Yang, X William

    2016-07-01

    Age of Huntington's disease (HD) motoric onset is strongly related to the number of CAG trinucleotide repeats in the huntingtin gene, suggesting that biological tissue age plays an important role in disease etiology. Recently, a DNA methylation based biomarker of tissue age has been advanced as an epigenetic aging clock. We sought to inquire if HD is associated with an accelerated epigenetic age. DNA methylation data was generated for 475 brain samples from various brain regions of 26 HD cases and 39 controls. Overall, brain regions from HD cases exhibit a significant epigenetic age acceleration effect (p=0.0012). A multivariate model analysis suggests that HD status increases biological age by 3.2 years. Accelerated epigenetic age can be observed in specific brain regions (frontal lobe, parietal lobe, and cingulate gyrus). After excluding controls, we observe a negative correlation (r=-0.41, p=5.5×10-8) between HD gene CAG repeat length and the epigenetic age of HD brain samples. Using correlation network analysis, we identify 11 co-methylation modules with a significant association with HD status across 3 broad cortical regions. In conclusion, HD is associated with an accelerated epigenetic age of specific brain regions and more broadly with substantial changes in brain methylation levels.

  20. Huntington's disease accelerates epigenetic aging of human brain and disrupts DNA methylation levels

    PubMed Central

    Horvath, Steve; Langfelder, Peter; Kwak, Seung; Aaronson, Jeff; Rosinski, Jim; Vogt, Thomas F.; Eszes, Marika; Faull, Richard L.M.; Curtis, Maurice A.; Waldvogel, Henry J.; Choi, Oi-Wa; Tung, Spencer; Vinters, Harry V.; Coppola, Giovanni; Yang, X. William

    2016-01-01

    Age of Huntington's disease (HD) motoric onset is strongly related to the number of CAG trinucleotide repeats in the huntingtin gene, suggesting that biological tissue age plays an important role in disease etiology. Recently, a DNA methylation based biomarker of tissue age has been advanced as an epigenetic aging clock. We sought to inquire if HD is associated with an accelerated epigenetic age. DNA methylation data was generated for 475 brain samples from various brain regions of 26 HD cases and 39 controls. Overall, brain regions from HD cases exhibit a significant epigenetic age acceleration effect (p=0.0012). A multivariate model analysis suggests that HD status increases biological age by 3.2 years. Accelerated epigenetic age can be observed in specific brain regions (frontal lobe, parietal lobe, and cingulate gyrus). After excluding controls, we observe a negative correlation (r=−0.41, p=5.5×10−8) between HD gene CAG repeat length and the epigenetic age of HD brain samples. Using correlation network analysis, we identify 11 co-methylation modules with a significant association with HD status across 3 broad cortical regions. In conclusion, HD is associated with an accelerated epigenetic age of specific brain regions and more broadly with substantial changes in brain methylation levels. PMID:27479945

  1. Accelerated aging test results for aerospace wire insulation constructions

    NASA Technical Reports Server (NTRS)

    Dunbar, William G.

    1995-01-01

    Several wire insulation constructions were evaluated with and without continuous glow discharges at low pressure and high temperature to determine the aging characteristics of acceptable wire insulation constructions. It was known at the beginning of the test program that insulation aging takes several years when operated at normal ambient temperature and pressure of 20 C and 760 torr. Likewise, it was known that the accelerated aging process decreases insulation life by approximately 50% for each 10 C temperature rise. Therefore, the first phases of the program, not reported in these test results, were to select wire insulation constructions that could operate at high temperature and low pressure for over 10,000 hours with negligible shrinkage and little materials' deterioration.The final phase of the program was to determine accelerated aging characteristics. When an insulation construction is subjected to partial discharges the insulation is locally heated by the bombardment of the discharges, the insulation is also subjected to ozone and other deteriorating gas particles that may significantly increase the aging process. Several insulation systems using either a single material or combinations of teflon, kapton, and glass insulation constructions were tested. All constructions were rated to be partial discharge and/or corona-free at 240 volts, 400 Hz and 260 C (500 F) for 50, 000 hours at altitudes equivalent to the Paschen law. Minimum partial discharge aging tests were preceded by screening tests lasting 20 hours at 260 C. The aging process was accelerated by subjecting the test articles to temperatures up to 370 C (700 F) with and without partial discharges. After one month operation with continuous glow discharges surrounding the test articles, most insulation systems were either destroyed or became brittle, cracked, and unsafe for use. Time with space radiation as with partial discharges is accumulative.

  2. Accelerated aging test results for aerospace wire insulation constructions

    NASA Astrophysics Data System (ADS)

    Dunbar, William G.

    1995-11-01

    Several wire insulation constructions were evaluated with and without continuous glow discharges at low pressure and high temperature to determine the aging characteristics of acceptable wire insulation constructions. It was known at the beginning of the test program that insulation aging takes several years when operated at normal ambient temperature and pressure of 20 C and 760 torr. Likewise, it was known that the accelerated aging process decreases insulation life by approximately 50% for each 10 C temperature rise. Therefore, the first phases of the program, not reported in these test results, were to select wire insulation constructions that could operate at high temperature and low pressure for over 10,000 hours with negligible shrinkage and little materials' deterioration.The final phase of the program was to determine accelerated aging characteristics. When an insulation construction is subjected to partial discharges the insulation is locally heated by the bombardment of the discharges, the insulation is also subjected to ozone and other deteriorating gas particles that may significantly increase the aging process. Several insulation systems using either a single material or combinations of teflon, kapton, and glass insulation constructions were tested. All constructions were rated to be partial discharge and/or corona-free at 240 volts, 400 Hz and 260 C (500 F) for 50, 000 hours at altitudes equivalent to the Paschen law. Minimum partial discharge aging tests were preceded by screening tests lasting 20 hours at 260 C. The aging process was accelerated by subjecting the test articles to temperatures up to 370 C (700 F) with and without partial discharges. After one month operation with continuous glow discharges surrounding the test articles, most insulation systems were either destroyed or became brittle, cracked, and unsafe for use. Time with space radiation as with partial discharges is accumulative.

  3. Associations of menstrual cycle irregularities with age, obesity and phenotype in patients with polycystic ovary syndrome.

    PubMed

    Panidis, Dimitrios; Tziomalos, Konstantinos; Papadakis, Efstathios; Chatzis, Panagiotis; Kandaraki, Eleni A; Tsourdi, Elena A; Macut, Djuro; Bjekic-Macut, Jelica; Marthopoulos, Apostolos; Katsikis, Ilias

    2015-01-01

    Limited data suggest that menstrual cycle abnormalities are more pronounced in younger and more obese patients with polycystic ovary syndrome (PCOS). We aimed to evaluate the association between menstrual cycle pattern and age, obesity and PCOS phenotype in a large population of women with PCOS. We studied 1,297 women with PCOS and divided them according to: a) age in ≤ 20, 21-30 and > 30 years old, b) body mass index in normal weight, overweight and obese and c) PCOS phenotype in phenotype 1 (anovulation, hyperandrogenemia and polycystic ovaries), 2 (anovulation and hyperandrogenemia without polycystic ovaries), 3 (hyperandrogenemia and polycystic ovaries without anovulation) and 4 (anovulation and polycystic ovaries without hyperandrogenemia). The proportion of women with regular menstrual cycles progressively increased in the older age groups, being 8.1, 10.5 and 12.7% in women ≤ 20, 21-30 and > 30 years old, respectively (p = 0.037). The proportion of women with regular menstrual cycles did not differ between normal weight and obese women but was higher in overweight women (9.3, 9.4 and 13%, respectively; p = 0.020). The proportion of women with regular cycles alternating with irregular cycles was highest in women with phenotype 4, intermediate in women with phenotype 2 and lowest in women with phenotype 1 (74.3, 69.4 and 61.7%, respectively; p = 0.027). Menstrual cycle pattern is more irregular in women with the "classic" PCOS phenotypes than in phenotype 4 but appears to normalize with ageing. On the other hand, obesity does not appear to have an important effect on menstrual cycle pattern in PCOS.

  4. The influences of accelerated aging on mechanical properties of veneering ceramics used for zirconia restorations.

    PubMed

    Luo, Huinan; Tang, Xuehua; Dong, Zhen; Tang, Hui; Nakamura, Takashi; Yatani, Hirofumi

    2016-01-01

    This study evaluated the influences of accelerated aging on the mechanical properties of veneering ceramics used for zirconia frameworks. Five different veneering ceramics for zirconia frameworks were used. Twenty specimens were fabricated for each veneering ceramic. All specimens were divided into two groups. One was subjected to accelerated aging and the other was used as a control. Accelerated aging was performed in distilled water for 5 h at 200ºC and 2 atm. The density, open porosity, surface roughness, three-point flexural strength, and Vickers hardness were measured. The results showed that the density, open porosity, and surface roughness of all examined veneering ceramics were changed by the accelerated aging process. Accelerated aging was also found to have a positive effect on strength and a negative effect on the hardness.

  5. Accelerated aging and stabilization of radiation-vulcanized EPDM rubber

    NASA Astrophysics Data System (ADS)

    Basfar, A. A.; Abdel-Aziz, M. M.; Mofti, S.

    2000-03-01

    The effect of different antioxidants and their mixtures on the thermal aging and accelerated weathering of γ-radiation vulcanized EPDM rubber in presence of crosslinking coagent, was investigated. The compounds used were either a synergistic blend of phenolic and phosphite antioxidants, i.e. 1:4 Irganox 1076: Irgafos 168 or a blend of arylamine and quinoline type antioxidants, i.e. 1:1 IPPD: TMQ, at fixed concentration. Tinuvin 622 LD hindered amine light stabilized (HALS) was also used. The response was evaluated by the tensile strength and elongation at break for irradiated samples after thermal aging at 100°C for 28 days and accelerated weathering (Xenon test) up to 200 h.

  6. Accelerated Aging Experiments for Prognostics of Damage Growth in Composite Materials

    DTIC Science & Technology

    2011-09-01

    possible resource to collect such data is an accelerated aging platform. To that end this paper describes a fatigue cycling experiment with the goal to...possible resource to collect such data is an accelerated aging platform. To that end this paper describes a fatigue cycling experiment with the goal to...suffer from two damage types: matrix micro-cracks and inter- laminar delamination. When subject to fatigue loading matrix micro-cracks develop in the

  7. Accelerated telomere shortening and replicative senescence in human fibroblasts overexpressing mutant and wild-type lamin A

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Huang Shurong; Risques, Rosa Ana; Martin, George M.

    2008-01-01

    LMNA mutations are responsible for a variety of genetic disorders, including muscular dystrophy, lipodystrophy, and certain progeroid syndromes, notably Hutchinson-Gilford Progeria. Although a number of clinical features of these disorders are suggestive of accelerated aging, it is not known whether cells derived from these patients exhibit cellular phenotypes associated with accelerated aging. We examined a series of isogenic skin fibroblast lines transfected with LMNA constructs bearing known pathogenic point mutations or deletion mutations found in progeroid syndromes. Fibroblasts overexpressing mutant lamin A exhibited accelerated rates of loss of telomeres and shortened replicative lifespans, in addition to abnormal nuclear morphology. Tomore » our surprise, these abnormalities were also observed in lines overexpressing wild-type lamin A. Copy number variants are common in human populations; those involving LMNA, whether arising meiotically or mitotically, might lead to progeroid phenotypes. In an initial pilot study of 23 progeroid cases without detectable WRN or LMNA mutations, however, no cases of altered LMNA copy number were detected. Nevertheless, our findings raise a hypothesis that changes in lamina organization may cause accelerated telomere attrition, with different kinetics for overexpession of wild-type and mutant lamin A, which leads to rapid replicative senescence and progroid phenotypes.« less

  8. Effect of accelerated aging on the viscoelastic properties of a medical grade silicone.

    PubMed

    Mahomed, Aziza; Hukins, David W L; Kukureka, Stephen N

    2015-01-01

    The viscoelastic properties of cylinders (diameter 5 mm, height 2.2 ± 0.2 mm) of Nagor silicone elastomer of medium hardness, were investigated before and after the specimens had undergone accelerated aging in saline solution at 70°C for 38, 76 and 114 days (to simulate aging at 37°C, for 1, 2 and 3 years, respectively). All sets of specimens were immersed in physiological saline solution at 37°C during testing and the properties were measured using dynamic mechanical analysis (DMA). A sinusoidal cyclic compression of 40 N ± 5 N was applied over a frequency range, f, of 0.02-25 Hz. Values of the storage, E', and loss, E″, moduli were found to depend on f; the dependence of E' or E″ on the logarithm (base 10) of f was represented by a second-order polynomial. After accelerated aging, the E' and E″ values did not increase significantly (p<0.05). Furthermore, scanning electron microscopy (SEM) showed that accelerated aging did not affect the surface morphology of silicone. Attenuated total reflectance Fourier transform infra-red spectroscopy (ATR-FTIR) showed that accelerated aging had a negligible effect on the surface chemical structures of the material. Differential scanning calorimetry (DSC) showed no changes to the bulk properties of silicone, following accelerated aging.

  9. Osteopontin attenuates aging-associated phenotypes of hematopoietic stem cells.

    PubMed

    Guidi, Novella; Sacma, Mehmet; Ständker, Ludger; Soller, Karin; Marka, Gina; Eiwen, Karina; Weiss, Johannes M; Kirchhoff, Frank; Weil, Tanja; Cancelas, Jose A; Florian, Maria Carolina; Geiger, Hartmut

    2017-04-03

    Upon aging, hematopoietic stem cells (HSCs) undergo changes in function and structure, including skewing to myeloid lineages, lower reconstitution potential and loss of protein polarity. While stem cell intrinsic mechanisms are known to contribute to HSC aging, little is known on whether age-related changes in the bone marrow niche regulate HSC aging. Upon aging, the expression of osteopontin (OPN) in the murine bone marrow stroma is reduced. Exposure of young HSCs to an OPN knockout niche results in a decrease in engraftment, an increase in long-term HSC frequency and loss of stem cell polarity. Exposure of aged HSCs to thrombin-cleaved OPN attenuates aging of old HSCs, resulting in increased engraftment, decreased HSC frequency, increased stem cell polarity and a restored balance of lymphoid and myeloid cells in peripheral blood. Thus, our data suggest a critical role for reduced stroma-derived OPN for HSC aging and identify thrombin-cleaved OPN as a novel niche informed therapeutic approach for ameliorating HSC phenotypes associated with aging. © 2017 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

  10. Pathway-based factor analysis of gene expression data produces highly heritable phenotypes that associate with age.

    PubMed

    Anand Brown, Andrew; Ding, Zhihao; Viñuela, Ana; Glass, Dan; Parts, Leopold; Spector, Tim; Winn, John; Durbin, Richard

    2015-03-09

    Statistical factor analysis methods have previously been used to remove noise components from high-dimensional data prior to genetic association mapping and, in a guided fashion, to summarize biologically relevant sources of variation. Here, we show how the derived factors summarizing pathway expression can be used to analyze the relationships between expression, heritability, and aging. We used skin gene expression data from 647 twins from the MuTHER Consortium and applied factor analysis to concisely summarize patterns of gene expression to remove broad confounding influences and to produce concise pathway-level phenotypes. We derived 930 "pathway phenotypes" that summarized patterns of variation across 186 KEGG pathways (five phenotypes per pathway). We identified 69 significant associations of age with phenotype from 57 distinct KEGG pathways at a stringent Bonferroni threshold ([Formula: see text]). These phenotypes are more heritable ([Formula: see text]) than gene expression levels. On average, expression levels of 16% of genes within these pathways are associated with age. Several significant pathways relate to metabolizing sugars and fatty acids; others relate to insulin signaling. We have demonstrated that factor analysis methods combined with biological knowledge can produce more reliable phenotypes with less stochastic noise than the individual gene expression levels, which increases our power to discover biologically relevant associations. These phenotypes could also be applied to discover associations with other environmental factors. Copyright © 2015 Brown et al.

  11. Effect of accelerated aging on the cross-link density of medical grade silicones.

    PubMed

    Mahomed, Aziza; Pormehr, Negin Bagheri

    2016-11-25

    Four specimens of Nagor silicone of different hardness (soft, medium and hard) were swollen, until they reached equilibrium (i.e. constant mass) in five liquids at 25°C, before and after accelerated aging. For the specimens swollen before accelerated aging, the greatest swelling was obtained in methyl cyclohexane, while for the specimens swollen after accelerated aging, the greatest swelling was obtained in cyclohexane. The cross-link density, υ, was also calculated from the swelling measurements for all the specimens, before and after accelerated aging, using the Flory-Rehner equation. The softer silicones, which swelled the most, had lower υ values than harder silicones. The amount of swelling (measured in terms of ϕ) and υ varied significantly (p<0.05) in some cases, between the different silicone hardness and between different liquids. Furthermore, the cross-link density, υ, significantly (p<0.05) increased after accelerated aging in most liquids.Note: ϕ is defined as the volume fraction of polymer in its equilibrium swollen state. A probability value of statistical significance of 0.05 or 5% was selected, hence if a p value of less than 0.05 was obtained, the null hypothesis was rejected (i.e. significant if p<0.05).

  12. Dietary restriction ameliorates haematopoietic ageing independent of telomerase, whilst lack of telomerase and short telomeres exacerbates the ageing phenotype.

    PubMed

    Al-Ajmi, Nouf; Saretzki, Gabriele; Miles, Colin; Spyridopoulos, Ioakim

    2014-10-01

    Ageing is associated with an overall decline in the functional capacity of tissues and stem cells, including haematopoietic stem and progenitor cells (HSPCs), as well as telomere dysfunction. Dietary restriction (DR) is a recognised anti-ageing intervention that extends lifespan and improves health in several organisms. To investigate the role of telomeres and telomerase in haematopoietic ageing, we compared the HSPC profile and clonogenic capacity of bone marrow cells from wild type with telomerase-deficient mice and the effect of DR on these parameters. Compared with young mice, aged wild type mice demonstrated a significant accumulation of HSPCs (1.3% vs 0.2%, P=0.002) and elevated numbers of granulocyte/macrophage colony forming units (CFU-GM, 26.4 vs 17.3, P=0.0037) consistent with myeloid "skewing" of haematopoiesis. DR was able to restrict the increase in HSPC number as well as the myeloid "skewing" in aged wild type mice. In order to analyse the influence of short telomeres on the ageing phenotype we examined mice lacking the RNA template for telomerase, TERC(-/-). Telomere shortening resulted in a similar bone marrow phenotype to that seen in aged mice, with significantly increased HSPC numbers and an increased formation of all myeloid colony types but at a younger age than wild type mice. However, an additional increase in erythroid colonies (BFU-E) was also evident. Mice lacking telomerase reverse transcriptase without shortened telomeres, TERT(-/-), also presented with augmented haematopoietic ageing which was ameliorated by DR, demonstrating that the effect of DR was not dependent on the presence of telomerase in HSPCs. We conclude that whilst shortened telomeres mimic some aspects of haematopoietic ageing, both shortened telomeres and the lack of telomerase produce specific phenotypes, some of which can be prevented by dietary restriction. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Phenotypic and Genotypic Characterisation of Inflammatory Bowel Disease Presenting Before the Age of 2 years

    PubMed Central

    Dziubak, Robert; Pescarin, Matilde; Drury, Suzanne; Godwin, Heather; Reeve, Kate; Chadokufa, Sibongile; Huggett, Bonita; Sider, Sara; James, Chela; Acton, Nikki; Cernat, Elena; Gasparetto, Marco; Noble-Jamieson, Gabi; Kiparissi, Fevronia; Elawad, Mamoun; Beales, Phil L.; Sebire, Neil J.; Gilmour, Kimberly; Uhlig, Holm H.; Bacchelli, Chiara; Shah, Neil

    2017-01-01

    Abstract Objectives: Inflammatory bowel disease [IBD] presenting in early childhood is extremely rare. More recently, progress has been made to identify children with monogenic forms of IBD predominantly presenting very early in life. In this study, we describe the heterogeneous phenotypes and genotypes of patients with IBD presenting before the age of 2 years and establish phenotypic features associated with underlying monogenicity. Methods: Phenotype data of 62 children with disease onset before the age of 2 years presenting over the past 20 years were reviewed. Children without previously established genetic diagnosis were prospectively recruited for next-generation sequencing. Results: In all, 62 patients [55% male] were identified. The median disease onset was 3 months of age (interquartile range [IQR]: 1 to 11). Conventional IBD classification only applied to 15 patients with Crohn’s disease [CD]-like [24%] and three with ulcerative colitis [UC]-like [5%] phenotype; 44 patients [71%] were diagnosed with otherwise unclassifiable IBD. Patients frequently required parenteral nutrition [40%], extensive immunosuppression [31%], haematopoietic stem-cell transplantation [29%], and abdominal surgery [19%]. In 31% of patients, underlying monogenic diseases were established [EPCAM, IL10, IL10RA, IL10RB, FOXP3, LRBA, SKIV2L, TTC37, TTC7A]. Phenotypic features significantly more prevalent in monogenic IBD were: consanguinity, disease onset before the 6th month of life, stunting, extensive intestinal disease and histological evidence of epithelial abnormalities. Conclusions: IBD in children with disease onset before the age of 2 years is frequently unclassifiable into Crohn’s disease and ulcerative colitis, particularly treatment resistant, and can be indistinguishable from monogenic diseases with IBD-like phenotype. PMID:27302973

  14. Accelerated White Matter Aging in Schizophrenia: Role of White Matter Blood Perfusion

    PubMed Central

    Chiappelli, Joshua; McMahon, Robert; Muellerklein, Florian; Wijtenburg, S. Andrea; White, Michael G.; Rowland, Laura M.; Hong, L. Elliot

    2014-01-01

    Elevated rate of age-related decline in white matter integrity, indexed by fractional anisotropy (FA) from diffusion tensor imaging, was reported in patients with schizophrenia. Its etiology is unknown. We hypothesized that a decline of blood perfusion to the white matter may underlie the accelerated age-related reduction in FA in schizophrenia. Resting white matter perfusion and FA were collected using pseudo-continuous arterial spin labeling and high-angular-resolution diffusion tensor imaging, respectively, in 50 schizophrenia patients and 70 controls (age=18-63 years). Main outcome measures were the diagnosis-by-age interaction on whole-brain white matter perfusion, and FA. Significant age-related decline in brain white matter perfusion and FA were present in both groups. Age-by-diagnosis interaction was significant for FA (p<0.001) but not white matter perfusion. Age-by-diagnosis interaction for FA values remained significant even after accounting for age-related decline in perfusion. Therefore, we replicated the finding of an increased rate of age-related white matter FA decline in schizophrenia, and observed a significant age-related decline in white matter blood perfusion, although the latter did not contribute to the accelerated age-related decline in FA. The results suggest that factors other than reduced perfusion account for the accelerated age-related decline in white matter integrity in schizophrenia. PMID:24680326

  15. Insights into accelerated aging of SSL luminaires

    NASA Astrophysics Data System (ADS)

    Davis, J. Lynn; Lamvik, Michael; Bittle, James; Shepherd, Sarah; Yaga, Robert; Baldasaro, Nick; Solano, Eric; Bobashev, Georgiy

    2013-09-01

    Although solid-state lighting (SSL) products are often intended to have product lifetimes of 15 years or more, the rapid change in technology has created a need for accelerated life tests (ALTs) that can be performed in the span of several months. A critical element of interpreting results from any systems-level ALT is understanding of the impact of the test environment on each component. Because of its ubiquity in electronics, the use of temperature-humidity environments as potential ALTs for SSL luminaires was investigated. Results from testing of populations of three commercial 6" downlights in environments of 85°C and 85% relative humidity (RH) and 75°C and 75% RH are reported. These test environments were found to accelerate lumen depreciation of the entire luminaire optical system, including LEDs, lenses, and reflectors. The effects of aging were found to depend strongly on both the optical materials that were used and the design of the luminaire; this shows that the lumen maintenance behavior of SSL luminaires must be addressed at the optical systems level. Temperature-Humidity ALTs can be a useful test in understand lumainaire depreciation provided that proper consideration is given to the different aging rates of various materials. Since the impact of the temperature-humidity environment varies among components of the optical system, uniform aging of all system components in a single test is difficult to achieve.

  16. Accelerated Aging Experiments for Capacitor Health Monitoring and Prognostics

    NASA Technical Reports Server (NTRS)

    Kulkarni, Chetan S.; Celaya, Jose Ramon; Biswas, Gautam; Goebel, Kai

    2012-01-01

    This paper discusses experimental setups for health monitoring and prognostics of electrolytic capacitors under nominal operation and accelerated aging conditions. Electrolytic capacitors have higher failure rates than other components in electronic systems like power drives, power converters etc. Our current work focuses on developing first-principles-based degradation models for electrolytic capacitors under varying electrical and thermal stress conditions. Prognostics and health management for electronic systems aims to predict the onset of faults, study causes for system degradation, and accurately compute remaining useful life. Accelerated life test methods are often used in prognostics research as a way to model multiple causes and assess the effects of the degradation process through time. It also allows for the identification and study of different failure mechanisms and their relationships under different operating conditions. Experiments are designed for aging of the capacitors such that the degradation pattern induced by the aging can be monitored and analyzed. Experimental setups and data collection methods are presented to demonstrate this approach.

  17. No Association between Variation in Longevity Candidate Genes and Aging-related Phenotypes in Oldest-old Danes.

    PubMed

    Soerensen, Mette; Nygaard, Marianne; Debrabant, Birgit; Mengel-From, Jonas; Dato, Serena; Thinggaard, Mikael; Christensen, Kaare; Christiansen, Lene

    2016-06-01

    In this study we explored the association between aging-related phenotypes previously reported to predict survival in old age and variation in 77 genes from the DNA repair pathway, 32 genes from the growth hormone 1/ insulin-like growth factor 1/insulin (GH/IGF-1/INS) signalling pathway and 16 additional genes repeatedly considered as candidates for human longevity: APOE, APOA4, APOC3, ACE, CETP, HFE, IL6, IL6R, MTHFR, TGFB1, SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. Altogether, 1,049 single nucleotide polymorphisms (SNPs) were genotyped in 1,088 oldest-old (age 92-93 years) Danes and analysed with phenotype data on physical functioning (hand grip strength), cognitive functioning (mini mental state examination and a cognitive composite score), activity of daily living and self-rated health. Five SNPs showed association to one of the phenotypes; however, none of these SNPs were associated with a change in the relevant phenotype over time (7 years of follow-up) and none of the SNPs could be confirmed in a replication sample of 1,281 oldest-old Danes (age 94-100). Hence, our study does not support association between common variation in the investigated longevity candidate genes and aging-related phenotypes consistently shown to predict survival. It is possible that larger sample sizes are needed to robustly reveal associations with small effect sizes. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Testing the hypothesis of accelerated cerebral white matter aging in schizophrenia and major depression.

    PubMed

    Kochunov, Peter; Glahn, David C; Rowland, Laura M; Olvera, Rene L; Winkler, Anderson; Yang, Yi-Hong; Sampath, Hemalatha; Carpenter, Will T; Duggirala, Ravindranath; Curran, Joanne; Blangero, John; Hong, L Elliot

    2013-03-01

    Elevated rate of aging-related biological and functional decline, termed "accelerated aging," is reported in patients with schizophrenia (SCZ) and major depressive disorder (MDD). We used diffusion tensor imaging derived fractional anisotropy (FA) as a biomarker of aging-related decline in white matter (WM) integrity to test the hypotheses of accelerated aging in SCZ and MDD. The SCZ cohort comprised 58 SCZ patients and 60 controls (aged 20-60 years). The MDD cohort comprised 136 MDD patients and 351 controls (aged 20-79 years). The main outcome measures were the diagnosis-by-age interaction on whole-brain-averaged WM FA values and FA values from 12 major WM tracts. Diagnosis-by-age interaction for the whole-brain average FA was significant for the SCZ (p = .04) but not the MDD (p = .80) cohort. Diagnosis-by-age interaction was nominally significant (p<.05) for five WM tracts for SCZ and for none of the tracts in the MDD cohort. Tract-specific heterochronicity of the onset of age-related decline in SCZ demonstrated strong negative correlations with the age-of-peak myelination and the rates of age-related decline obtained from normative sample (r =-.61 and-.80, p<.05, respectively). No such trends existed for MDD cohort. Cerebral WM showed accelerated aging in SCZ but not in MDD, suggesting some difference in the pathophysiology underlying their WM aging changes. Tract-specific heterochronicity of WM development modulated presentation of accelerated aging in SCZ: WM tracts that matured later in life appeared more sensitive to the pathophysiology of SCZ and demonstrated more susceptibility to disorder-related accelerated decline in FA values with age. This trend was not observed in MDD cohort. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  19. Testing the hypothesis of accelerated cerebral white matter aging in schizophrenia and major depression

    PubMed Central

    Kochunov, P.; Glahn, D.C.; Rowland, L.M.; Olvera, R.L.; Winkler, A; Yang, Y.H.; Sampath, H.; Carpenter, W.T.; Dugarrila, R.; Curran, J.; Blangero, J.; Hong, L.E.

    2012-01-01

    Introduction Elevated rate of aging-related biological and functional decline, termed accelerated aging, is reported in patients with schizophrenia (SCZ) and major depressive disorder (MDD). We used diffusion tensor imaging (DTI) derived fractional anisotropy (FA) as biomarkers of aging-related decline in white matter (WM) integrity to test the hypotheses of accelerated aging in SCZ and MDD. Methods The SCZ cohort was composed of 58/60 SCZ patients/controls (age=20–60years). MDD cohort was composed of 136/351 MDD patients/controls (age=20–79years). Main outcome measures were the diagnosis-by-age interaction on whole-brain-averaged WM FA values and FA values from twelve major WM tracts. Results Diagnosis-by-age interaction for the whole-brain average FA was significant for the SCZ (p=0.04) but not in MDD cohort (p=0.80). Diagnosis-by-age interaction was nominally significant (p<0.05) for five WM tracts for SCZ and for none of the tracts in the MDD cohort. Tract-specific heterochronicity of the onset of age-related decline in SCZ demonstrated strong negative correlations with the age-of- peak myelination and the rates of age-related decline obtained from normative sample (r=−0.61 and −0.80, p<0.05, respectively). No such trends existed for MDD cohort. Conclusion Cerebral WM showed accelerated aging in SCZ but not in MDD, suggesting some difference in the pathophysiology underlying their WM aging changes. Tract-specific heterochronicity of WM development modulated presentation of accelerated aging in SCZ: white matter tracts that matured later in life appeared more sensitive to the pathophysiology of SCZ and demonstrated more susceptibility to disorder-related accelerated decline in FA values with age. This trend was not observed in MDD cohort. PMID:23200529

  20. Age-related epigenetic drift and phenotypic plasticity loss: implications in prevention of age-related human diseases

    PubMed Central

    Li, Yuanyuan; Tollefsbol, Trygve O

    2016-01-01

    Aging is considered as one of the most important developmental processes in organisms and is closely associated with global deteriorations of epigenetic markers such as aberrant methylomic patterns. This altered epigenomic state, referred to ‘epigenetic drift’, reflects deficient maintenance of epigenetic marks and contributes to impaired cellular and molecular functions in aged cells. Epigenetic drift-induced abnormal changes during aging are scantily repaired by epigenetic modulators. This inflexibility in the aged epigenome may lead to an age-related decline in phenotypic plasticity at the cellular and molecular levels due to epigenetic drift. This perspective aims to provide novel concepts for understanding epigenetic effects on the aging process and to provide insights into epigenetic prevention and therapeutic strategies for age-related human disease. PMID:27882781

  1. Accelerated ageing and renal dysfunction links lower socioeconomic status and dietary phosphate intake.

    PubMed

    McClelland, Ruth; Christensen, Kelly; Mohammed, Suhaib; McGuinness, Dagmara; Cooney, Josephine; Bakshi, Andisheh; Demou, Evangelia; MacDonald, Ewan; Caslake, Muriel; Stenvinkel, Peter; Shiels, Paul G

    2016-05-01

    We have sought to explore the impact of dietary Pi intake on human age related health in the pSoBid cohort (n=666) to explain the disparity between health and deprivation status in this cohort. As hyperphosphataemia is a driver of accelerated ageing in rodent models of progeria we tested whether variation in Pi levels in man associate with measures of biological ageing and health. We observed significant relationships between serum Pi levels and markers of biological age (telomere length (p=0.040) and DNA methylation content (p=0.028), gender and chronological age (p=0.032). When analyses were adjusted for socio-economic status and nutritional factors, associations were observed between accelerated biological ageing (telomere length, genomic methylation content) and dietary derived Pi levels among the most deprived males, directly related to the frequency of red meat consumption. Accelerated ageing is associated with high serum Pi levels and frequency of red meat consumption. Our data provide evidence for a mechanistic link between high intake of Pi and age-related morbidities tied to socio-economic status.

  2. Phenotypic and Genotypic Characterisation of Inflammatory Bowel Disease Presenting Before the Age of 2 years.

    PubMed

    Kammermeier, Jochen; Dziubak, Robert; Pescarin, Matilde; Drury, Suzanne; Godwin, Heather; Reeve, Kate; Chadokufa, Sibongile; Huggett, Bonita; Sider, Sara; James, Chela; Acton, Nikki; Cernat, Elena; Gasparetto, Marco; Noble-Jamieson, Gabi; Kiparissi, Fevronia; Elawad, Mamoun; Beales, Phil L; Sebire, Neil J; Gilmour, Kimberly; Uhlig, Holm H; Bacchelli, Chiara; Shah, Neil

    2017-01-01

    Inflammatory bowel disease [IBD] presenting in early childhood is extremely rare. More recently, progress has been made to identify children with monogenic forms of IBD predominantly presenting very early in life. In this study, we describe the heterogeneous phenotypes and genotypes of patients with IBD presenting before the age of 2 years and establish phenotypic features associated with underlying monogenicity. Phenotype data of 62 children with disease onset before the age of 2 years presenting over the past 20 years were reviewed. Children without previously established genetic diagnosis were prospectively recruited for next-generation sequencing. In all, 62 patients [55% male] were identified. The median disease onset was 3 months of age (interquartile range [IQR]: 1 to 11). Conventional IBD classification only applied to 15 patients with Crohn's disease [CD]-like [24%] and three with ulcerative colitis [UC]-like [5%] phenotype; 44 patients [71%] were diagnosed with otherwise unclassifiable IBD. Patients frequently required parenteral nutrition [40%], extensive immunosuppression [31%], haematopoietic stem-cell transplantation [29%], and abdominal surgery [19%]. In 31% of patients, underlying monogenic diseases were established [EPCAM, IL10, IL10RA, IL10RB, FOXP3, LRBA, SKIV2L, TTC37, TTC7A]. Phenotypic features significantly more prevalent in monogenic IBD were: consanguinity, disease onset before the 6th month of life, stunting, extensive intestinal disease and histological evidence of epithelial abnormalities. IBD in children with disease onset before the age of 2 years is frequently unclassifiable into Crohn's disease and ulcerative colitis, particularly treatment resistant, and can be indistinguishable from monogenic diseases with IBD-like phenotype. Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  3. Brain-Derived Neurotrophic Factor Expression in Individuals With Schizophrenia and Healthy Aging: Testing the Accelerated Aging Hypothesis of Schizophrenia.

    PubMed

    Islam, Farhana; Mulsant, Benoit H; Voineskos, Aristotle N; Rajji, Tarek K

    2017-07-01

    Schizophrenia has been hypothesized to be a syndrome of accelerated aging. Brain plasticity is vulnerable to the normal aging process and affected in schizophrenia: brain-derived neurotrophic factor (BDNF) is an important neuroplasticity molecule. The present review explores the accelerated aging hypothesis of schizophrenia by comparing changes in BDNF expression in schizophrenia with aging-associated changes. Individuals with schizophrenia show patterns of increased overall mortality, metabolic abnormalities, and cognitive decline normally observed later in life in the healthy population. An overall decrease is observed in BDNF expression in schizophrenia compared to healthy controls and in older individuals compared to a younger cohort. There is a marked decrease in BDNF levels in the frontal regions and in the periphery among older individuals and those with schizophrenia; however, data for BDNF expression in the occipital, parietal, and temporal cortices and the hippocampus is inconclusive. Accelerated aging hypothesis is supported based on frontal regions and peripheral studies; however, further studies are needed in other brain regions.

  4. Is Chronic Obstructive Pulmonary Disease an Accelerated Aging Disease?

    PubMed

    MacNee, William

    2016-12-01

    Aging is one of the most important risk factors for most chronic diseases. The worldwide increase in life expectancy has been accompanied by an increase in the prevalence of age-related diseases that result in significant morbidity and mortality and place an enormous burden on healthcare and resources. Aging is a progressive degeneration of the tissues that has a negative impact on the structure and function of vital organs. The lung ages, resulting in decreased function and reduced capacity to respond to environmental stresses and injury. Many of the changes that occur in the lungs with normal aging, such as decline in lung function, increased gas trapping, loss of lung elastic recoil, and enlargement of the distal air spaces, also are present in chronic obstructive pulmonary disease (COPD). The prevalence of COPD is two to three times higher in people over the age of 60 years than in younger age groups. Indeed, COPD has been considered a condition of accelerated lung aging. Several mechanisms associated with aging are present in the lungs of patients with COPD. Cell senescence is present in emphysematous lungs and is associated with shortened telomeres and decreased antiaging molecules, suggesting accelerated aging in the lungs of patients with COPD. Increasing age leads to elevated basal levels of inflammation and oxidative stress (inflammaging) and to increased immunosenescence associated with changes in both the innate and adaptive immune responses. These changes are similar to those that occur in COPD and may enhance the activity of the disease as well as increase susceptibility to exacerbations in patients with COPD. Understanding the mechanism of age-related changes in COPD may identify novel therapies for this condition.

  5. Pathway-Based Factor Analysis of Gene Expression Data Produces Highly Heritable Phenotypes That Associate with Age

    PubMed Central

    Anand Brown, Andrew; Ding, Zhihao; Viñuela, Ana; Glass, Dan; Parts, Leopold; Spector, Tim; Winn, John; Durbin, Richard

    2015-01-01

    Statistical factor analysis methods have previously been used to remove noise components from high-dimensional data prior to genetic association mapping and, in a guided fashion, to summarize biologically relevant sources of variation. Here, we show how the derived factors summarizing pathway expression can be used to analyze the relationships between expression, heritability, and aging. We used skin gene expression data from 647 twins from the MuTHER Consortium and applied factor analysis to concisely summarize patterns of gene expression to remove broad confounding influences and to produce concise pathway-level phenotypes. We derived 930 “pathway phenotypes” that summarized patterns of variation across 186 KEGG pathways (five phenotypes per pathway). We identified 69 significant associations of age with phenotype from 57 distinct KEGG pathways at a stringent Bonferroni threshold (P<5.38×10−5). These phenotypes are more heritable (h2=0.32) than gene expression levels. On average, expression levels of 16% of genes within these pathways are associated with age. Several significant pathways relate to metabolizing sugars and fatty acids; others relate to insulin signaling. We have demonstrated that factor analysis methods combined with biological knowledge can produce more reliable phenotypes with less stochastic noise than the individual gene expression levels, which increases our power to discover biologically relevant associations. These phenotypes could also be applied to discover associations with other environmental factors. PMID:25758824

  6. Diverse Application of Magnetic Resonance Imaging for Mouse Phenotyping

    PubMed Central

    Wu, Yijen L.; Lo, Cecilia W.

    2017-01-01

    Small animal models, particularly mouse models, of human diseases are becoming an indispensable tool for biomedical research. Studies in animal models have provided important insights into the etiology of diseases and accelerated the development of therapeutic strategies. Detailed phenotypic characterization is essential, both for the development of such animal models and mechanistic studies into disease pathogenesis and testing the efficacy of experimental therapeutics. Magnetic Resonance Imaging (MRI) is a versatile and non-invasive imaging modality with excellent penetration depth, tissue coverage, and soft tissue contrast. MRI, being a multi-modal imaging modality, together with proven imaging protocols and availability of good contrast agents, is ideally suited for phenotyping mutant mouse models. Here we describe the applications of MRI for phenotyping structural birth defects involving the brain, heart, and kidney in mice. The versatility of MRI and its ease of use are well suited to meet the rapidly increasing demands for mouse phenotyping in the coming age of functional genomics. PMID:28544650

  7. Dietary and genetic evidence for phosphate toxicity accelerating mammalian aging

    PubMed Central

    Ohnishi, Mutsuko; Razzaque, M. Shawkat

    2010-01-01

    Identifying factors that accelerate the aging process can provide important therapeutic targets for slowing down this process. Misregulation of phosphate homeostasis has been noted in various skeletal, cardiac, and renal diseases, but the exact role of phosphate toxicity in mammalian aging is not clearly defined. Phosphate is widely distributed in the body and is involved in cell signaling, energy metabolism, nucleic acid synthesis, and the maintenance of acid-base balance by urinary buffering. In this study, we used an in vivo genetic approach to determine the role of phosphate toxicity in mammalian aging. Klotho-knockout mice (klotho−/−) have a short life span and show numerous physical, biochemical, and morphological features consistent with premature aging, including kyphosis, uncoordinated movement, hypogonadism, infertility, severe skeletal muscle wasting, emphysema, and osteopenia, as well as generalized atrophy of the skin, intestine, thymus, and spleen. Molecular and biochemical analyses suggest that increased renal activity of sodium-phosphate cotransporters (NaPi2a) leads to severe hyperphosphatemia in klotho−/− mice. Genetically reducing serum phosphate levels in klotho−/− mice by generating a NaPi2a and klotho double-knockout (NaPi2a−/−/klotho−/−) strain resulted in amelioration of premature aging-like features. The NaPi2a−/−/klotho−/− double-knockout mice regained reproductive ability, recovered their body weight, reduced their organ atrophy, and suppressed ectopic calcifications, with the resulting effect being prolonged survival. More important, when hyperphosphatemia was induced in NaPi2a−/−/klotho−/− mice by feeding with a high-phosphate diet, premature aging-like features reappeared, clearly suggesting that phosphate toxicity is the main cause of premature aging in klotho−/− mice. The results of our dietary and genetic manipulation studies provide in vivo evidence for phosphate toxicity accelerating the

  8. Insights into accelerated aging of SSL luminaires

    DOE PAGES

    Davis, J. Lynn; Lamvik, Michael; Bittle, James; ...

    2013-09-30

    Although solid-state lighting (SSL) products are often intended to have product lifetimes of 15 years or more, the rapid change in technology has created a need for accelerated life tests (ALTs) that can be performed in the span of several months. A critical element of interpreting results from any systems-level ALT is understanding of the impact of the test environment on each component. Because of its ubiquity in electronics, the use of temperature-humidity environments as potential ALTs for SSL luminaires was investigated. Results from testing of populations of three commercial 6” downlights in environments of 85oC and 85% relative humiditymore » (RH) and 75oC and 75% RH are reported. These test environments were found to accelerate lumen depreciation of the entire luminaire optical system, including LEDs, lenses, and reflectors. The effects of aging were found to depend strongly on both the optical materials that were used and the design of the luminaire; this shows that the lumen maintenance behavior of SSL luminaires must be addressed at the optical systems level. Temperature-Humidity ALTs can be a useful test in understand lumainaire depreciation provided that proper consideration is given to the different aging rates of various materials. Since the impact of the temperature-humidity environment varies among components of the optical system, uniform aging of all system components in a single test is difficult to achieve.« less

  9. Body Acceleration as Indicator for Walking Economy in an Ageing Population.

    PubMed

    Valenti, Giulio; Bonomi, Alberto G; Westerterp, Klaas R

    2015-01-01

    In adults, walking economy declines with increasing age and negatively influences walking speed. This study aims at detecting determinants of walking economy from body acceleration during walking in an ageing population. 35 healthy elderly (18 males, age 51 to 83 y, BMI 25.5±2.4 kg/m2) walked on a treadmill. Energy expenditure was measured with indirect calorimetry while body acceleration was sampled at 60Hz with a tri-axial accelerometer (GT3X+, ActiGraph), positioned on the lower back. Walking economy was measured as lowest energy needed to displace one kilogram of body mass for one meter while walking (WCostmin, J/m/kg). Gait features were extracted from the acceleration signal and included in a model to predict WCostmin. On average WCostmin was 2.43±0.42 J/m/kg and correlated significantly with gait rate (r2 = 0.21, p<0.01) and regularity along the frontal (anteroposterior) and lateral (mediolateral) axes (r2 = 0.16, p<0.05 and r2 = 0.12, p<0.05 respectively). Together, the three variables explained 46% of the inter-subject variance (p<0.001) with a standard error of estimate of 0.30 J/m/kg. WCostmin and regularity along the frontal and lateral axes were related to age (WCostmin: r2 = 0.44, p<0.001; regularity: r2 = 0.16, p<0.05 and r2 = 0.12, p<0.05 respectively frontal and lateral). The age associated decline in walking economy is induced by the adoption of an increased gait rate and by irregular body acceleration in the horizontal plane.

  10. Combined effects of aging and inflammation on renin-angiotensin system mediate mitochondrial dysfunction and phenotypic changes in cardiomyopathies.

    PubMed

    Burks, Tyesha N; Marx, Ruth; Powell, Laura; Rucker, Jasma; Bedja, Djahida; Heacock, Elisa; Smith, Barbara J; Foster, D Brian; Kass, David; O'Rourke, Brian; Walston, Jeremy D; Abadir, Peter M

    2015-05-20

    Although the effects of aging and inflammation on the health of the cardiac muscle are well documented, the combined effects of aging and chronic inflammation on cardiac muscle are largely unknown. The renin-angiotensin system (RAS) has been linked independently to both aging and inflammation, but is understudied in the context of their collective effect. Thus, we investigated localized cardiac angiotensin II type I and type II receptors (AT(1)R, AT(2)R), downstream effectors, and phenotypic outcomes using mouse models of the combination of aging and inflammation and compared it to a model of aging and a model of inflammation. We show molecular distinction in the combined effect of aging and inflammation as compared to each independently. The combination maintained an increased AT(1)R:AT(2)R and expression of Nox2 and exhibited the lowest activity of antioxidants. Despite signaling pathway differences, the combined effect shared phenotypic similarities with aging including oxidative damage, fibrosis, and hypertrophy. These phenotypic similarities have dubbed inflammatory conditions as premature aging, but they are, in fact, molecularly distinct. Moreover, treatment with an AT(1)R blocker, losartan, selectively reversed the signaling changes and ameliorated adverse phenotypic effects in the combination of aging and inflammation as well as each independently.

  11. Combined effects of aging and inflammation on renin-angiotensin system mediate mitochondrial dysfunction and phenotypic changes in cardiomyopathies

    PubMed Central

    Burks, Tyesha N.; Marx, Ruth; Powell, Laura; Rucker, Jasma; Bedja, Djahida; Heacock, Elisa; Smith, Barbara J.; Foster, D. Brian; Kass, David; O'Rourke, Brian; Walston, Jeremy D.; Abadir, Peter M.

    2015-01-01

    Although the effects of aging and inflammation on the health of the cardiac muscle are well documented, the combined effects of aging and chronic inflammation on cardiac muscle are largely unknown. The renin-angiotensin system (RAS) has been linked independently to both aging and inflammation, but is understudied in the context of their collective effect. Thus, we investigated localized cardiac angiotensin II type I and type II receptors (AT1R, AT2R), downstream effectors, and phenotypic outcomes using mouse models of the combination of aging and inflammation and compared it to a model of aging and a model of inflammation. We show molecular distinction in the combined effect of aging and inflammation as compared to each independently. The combination maintained an increased AT1R:AT2R and expression of Nox2 and exhibited the lowest activity of antioxidants. Despite signaling pathway differences, the combined effect shared phenotypic similarities with aging including oxidative damage, fibrosis, and hypertrophy. These phenotypic similarities have dubbed inflammatory conditions as premature aging, but they are, in fact, molecularly distinct. Moreover, treatment with an AT1R blocker, losartan, selectively reversed the signaling changes and ameliorated adverse phenotypic effects in the combination of aging and inflammation as well as each independently. PMID:26221650

  12. Schwann Cell Phenotype Changes in Aging Human Dental Pulp.

    PubMed

    Couve, E; Lovera, M; Suzuki, K; Schmachtenberg, O

    2018-03-01

    Schwann cells are glial cells that support axonal development, maintenance, defense, and regeneration in the peripheral nervous system. There is limited knowledge regarding the organization, plasticity, and aging of Schwann cells within the dental pulp in adult permanent teeth. The present study sought to relate changes in the pattern of Schwann cell phenotypes between young and old adult teeth with neuronal, immune, and vascular components of the dental pulp. Schwann cells are shown to form a prominent glial network at the dentin-pulp interface, consisting of nonmyelinating and myelinating phenotypes, forming a multicellular neuroimmune interface in association with nerve fibers and dendritic cells. Schwann cell phenotypes are recognized by the expression of S100, glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), Sox10, GAP43, and p75NTR markers. In young adult teeth, a dense population of nonmyelinating Schwann cells projects processes in close association with sensory nerve terminals through the odontoblast layer, reaching the adjacent predentin/dentin domain. While GAP43 and p75NTR are highly expressed in nonmyelinating Schwann cells from young adult teeth, the presence of these markers declines significantly in old adult teeth. Myelinated axons, identified by MBP expression, are mainly present at the Raschkow plexus and within nerve bundles in the dental pulp, but their density is significantly reduced in old adult versus young adult teeth. These data reveal age-related changes within the glial network of the dental pulp, in association with a reduction of coronal dental pulp innervation in old adult versus young adult teeth. The prominence of Schwann cells as a cellular component at the dentin-pulp interface supports the notion that their association with sensory nerve terminals and immune system components forms part of an integrated multicellular barrier for defense against pathogens and dentin repair.

  13. Accelerated aging-related transcriptome changes in the female prefrontal cortex

    PubMed Central

    Yuan, Yuan; Chen, Yi-Ping Phoebe; Boyd-Kirkup, Jerome; Khaitovich, Philipp; Somel, Mehmet

    2012-01-01

    Human female life expectancy is higher than that of males. Intriguingly, it has been reported that women display faster rates of age-related cognitive decline and a higher prevalence of Alzheimer’s disease (AD). To assess the molecular bases of these contradictory trends, we analyzed differences in expression changes with age between adult males and females, in four brain regions. In the superior frontal gyrus (SFG), a part of the prefrontal cortex, we observed manifest differences between the two sexes in the timing of age-related changes, that is, sexual heterochrony. Intriguingly, age-related expression changes predominantly occurred earlier, or at a faster pace, in females compared to men. These changes included decreased energy production and neural function and up-regulation of the immune response, all major features of brain aging. Furthermore, we found that accelerated expression changes in the female SFG correlated with expression changes observed in AD, as well as stress effects in the frontal cortex. Accelerated aging-related changes in the female SFG transcriptome may provide a link between a higher stress exposure or sensitivity in women and the higher prevalence of AD. PMID:22783978

  14. [PSYCHO PHYSIOLOGICAL MARKERS OF ACCELERATED AGING AMONG THOSE WORKING WITH OCCUPATIONAL HAZARDS].

    PubMed

    Bashkireva, A S; Kachan, Ye Yu; Kulapina, M E

    2015-01-01

    Using comparative analysis of two occupational groups we assessed the significance of psycho physiological markers of short-term memory accelerated aging in order to reveal how the age-related changes and working process affect mental work capacity. We revealed peculiarities of systemic structure of functions which determine mental work capacity depending on the age and length of service in lorry drivers. It was proved that age and long driving experience affect mnestic functions which show up quantitative and qualitative changes such as reduced volume of memorized information, longer time needed to memorize it, and tendency to diminished accuracy of memorization. We also proved that premature age-related changes of psycho physiological indices in drivers are the "risk indicators", while long driving experience is a real risk factor contributing to the acceleration of aging.

  15. C-reactive protein and familial risk for dementia: a phenotype for successful cognitive aging.

    PubMed

    Silverman, Jeremy M; Schmeidler, James; Beeri, Michal S; Rosendorff, Clive; Sano, Mary; Grossman, Hillel T; Carrión-Baralt, José R; Bespalova, Irina N; West, Rebecca; Haroutunian, Vahram

    2012-09-11

    Identifying phenotypes for successful cognitive aging, intact cognition into late-old age (>age 75), can help identify genes and neurobiological systems that may lead to interventions against and prevention of late-life cognitive impairment. The association of C-reactive protein (CRP) with cognitive impairment and dementia, observed primarily in young-elderly samples, appears diminished or reversed in late-old age (75+ years). A family history study determined if high CRP levels in late-old aged cognitively intact probands are associated with a reduced risk of dementia in their first-degree family members, suggesting a familial successful cognitive aging phenotype. The primary sample was 1,329 parents and siblings of 277 cognitively intact male veteran probands at least 75 years old. The replication sample was 202 relatives of 51 cognitively intact community-ascertained probands at least 85 years old. Relatives were assessed for dementia by proband informant interview. Their hazard ratio (HR) for dementia as a function of the proband's log-transformed CRP was calculated using the proportional hazards model. Covarying for key demographics, higher CRP in probands was strongly associated with lower risk of dementia in relatives (HR = 0.55 [95% confidence interval (CI) 0.41, 0.74], p < 0.02). The replication sample relationship was in the same direction, stronger in magnitude, and also significant (HR = 0.15 [95% CI 0.06, 0.37], p < 0.0001). Relatives of successful cognitive aging individuals with high levels of CRP are relatively likely to remain free of dementia. High CRP in successful cognitive aging individuals may constitute a phenotype for familial-and thus possibly genetic-successful cognitive aging.

  16. The queen's gut refines with age: longevity phenotypes in a social insect model.

    PubMed

    Anderson, Kirk E; Ricigliano, Vincent A; Mott, Brendon M; Copeland, Duan C; Floyd, Amy S; Maes, Patrick

    2018-06-18

    In social insects, identical genotypes can show extreme lifespan variation providing a unique perspective on age-associated microbial succession. In honey bees, short- and long-lived host phenotypes are polarized by a suite of age-associated factors including hormones, nutrition, immune senescence, and oxidative stress. Similar to other model organisms, the aging gut microbiota of short-lived (worker) honey bees accrue Proteobacteria and are depleted of Lactobacillus and Bifidobacterium, consistent with a suite of host senescence markers. In contrast, long-lived (queen) honey bees maintain youthful cellular function with much lower expression of oxidative stress genes, suggesting a very different host environment for age-associated microbial succession. We sequenced the microbiota of 63 honey bee queens exploring two chronological ages and four alimentary tract niches. To control for genetic and environmental variation, we quantified carbonyl accumulation in queen fat body tissue as a proxy for biological aging. We compared our results to the age-specific microbial succession of worker guts. Accounting for queen source variation, two or more bacterial species per niche differed significantly by queen age. Biological aging in queens was correlated with microbiota composition highlighting the relationship of microbiota with oxidative stress. Queens and workers shared many major gut bacterial species, but differ markedly in community structure and age succession. In stark contrast to aging workers, carbonyl accumulation in queens was significantly associated with increased Lactobacillus and Bifidobacterium and depletion of various Proteobacteria. We present a model system linking changes in gut microbiota to diet and longevity, two of the most confounding variables in human microbiota research. The pattern of age-associated succession in the queen microbiota is largely the reverse of that demonstrated for workers. The guts of short-lived worker phenotypes are

  17. Accelerated optical polymer aging studies for LED luminaire applications

    NASA Astrophysics Data System (ADS)

    Estupiñán, Edgar; Wendling, Peter; Kostrun, Marijan; Garner, Richard

    2013-09-01

    There is a need in the lighting industry to design and implement accelerated aging methods that accurately simulate the aging process of LED luminaire components. In response to this need, we have built a flexible and reliable system to study the aging characteristics of optical polymer materials, and we have employed it to study a commercially available LED luminaire diffuser made of PMMA. The experimental system consists of a "Blue LED Emitter" and a working surface. Both the temperatures of the samples and the optical powers of the LEDs are appropriately characterized in the system. Several accelerated aging experiments are carried out at different temperatures and optical powers over a 90 hour period and the measured transmission values are used as inputs to a degradation model derived using plausibility arguments. This model seems capable of predicting the behavior of the material as a function of time, temperature and optical power. The model satisfactorily predicts the measured transmission values of diffusers aged in luminaires at two different times and thus can be used to make application recommendations for this material. Specifically, at 35000 hours (the manufacturer's stated life of the luminaire) and at the typical operational temperature of the diffuser, the model predicts a transmission loss of only a few percent over the original transmission of the material at 450 nm, which renders this material suitable for this application.

  18. Premature Aging Phenotype in Mice Lacking High-Affinity Nicotinic Receptors: Region-Specific Changes in Layer V Pyramidal Cell Morphology.

    PubMed

    Konsolaki, Eleni; Skaliora, Irini

    2015-08-01

    The mechanisms by which aging leads to alterations in brain structure and cognitive deficits are unclear. Α deficient cholinergic system has been implicated as one of the main factors that could confer a heightened vulnerability to the aging process, and mice lacking high-affinity nicotinic receptors (β2(-/-)) have been proposed as an animal model of accelerated cognitive aging. To date, however, age-related changes in neuronal microanatomy have not been studied in these mice. In the present study, we examine the neuronal structure of yellow fluorescent protein (YFP(+)) layer V neurons in 2 cytoarchitectonically distinct cortical regions in wild-type (WT) and β2(-/-) animals. We find that (1) substantial morphological differences exist between YFP(+) cells of the anterior cingulate cortex (ACC) and primary visual cortex (V1), in both genotypes; (2) in WT animals, ACC cells are more susceptible to aging compared with cells in V1; and (3) β2 deletion is associated with a regionally and temporally specific increase in vulnerability to aging. ACC cells exhibit a prematurely aged phenotype already at 4-6 months, whereas V1 cells are spared in adulthood but strongly affected in old animals. Collectively, our data reveal region-specific synergistic effects of aging and genotype and suggest distinct vulnerabilities in V1 and ACC neurons. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  19. In vitro cytotoxicity of maxillofacial silicone elastomers: effect of accelerated aging.

    PubMed

    Bal, Bilge Turhan; Yilmaz, Handan; Aydin, Cemal; Karakoca, Seçil; Yilmaz, Sükran

    2009-04-01

    The purpose of this in vitro study was to evaluate the cytotoxicity of three maxillofacial silicone elastomers at 24, 48, and 72 h on L-929 cells and to determine the effect of accelerated aging on the cytotoxicity of these silicone elastomers. Disc-shaped test samples of maxillofacial silicone elastomers (Cosmesil, Episil, Multisil) were fabricated according to manufacturers' instructions under aseptic conditions. Samples were then divided into three groups: (1) not aged; (2) aged for 150 h with an accelerated weathering tester; and (3) aged for 300 h. Then the samples were placed in Dulbecco's Modified Eagle Medium/Ham's F12 (DMEM/F12) for 24, 48, and 72 h. After the incubation periods, cytotoxicity of the extracts to cultured fibroblasts (L-929) was measured by MTT assay. The degree of cytotoxicity of each sample was determined according to the reference value represented by the cells with a control (culture without sample). Statistical significance was determined by repeated measurement ANOVA (p < 0.01) followed by Duncan's test (p < 0.05). All test materials in each group demonstrated high survival rates in MTT assay (Episil; 93.84%, Multisil; 88.30%, Cosmesil; 87.50%, respectively); however, in all groups, Episil material demonstrated significantly higher cell survival rate after each of the experimental incubation periods (p < 0.05). Accelerated aging for 150 and 300 h had no significant effect on the biocompatibility of maxillofacial silicone elastomers tested (p > 0.05).

  20. [PSYCHO PHYSIOLOGICAL MARKERS OF ACCELERATED AGING AMONG THOSE WORKING WITH OCCUPATIONAL HAZARDS].

    PubMed

    Bashkireva, A S; Kachan, Ye Yu; Kulapina, M E

    2015-01-01

    We assessed the significance of psycho physiological markers of accelerated aging of the function of attention using comparative analysis of two occupational groups in order to reveal how the working process affects mental work capacity. We revealed peculiarities of systemic structure of functions which determine mental work capacity depending on the age and length of service in lorry drivers. It was proved that decrease in the mnestic functions of lorry-drivers takes place 10-15 years earlier compared to the control group. Psycho physiological indices, reflecting the functioning of attention, decreased not only with aging but also with longer driving experience. Our results show that it is necessary to conduct further studies of psycho physiological markers of age-related decrease in short-term memory depending on the activities at work in order to prevent accelerated aging and achieve professional longevity.

  1. When stem cells grow old: phenotypes and mechanisms of stem cell aging

    PubMed Central

    Schultz, Michael B.; Sinclair, David A.

    2016-01-01

    All multicellular organisms undergo a decline in tissue and organ function as they age. An attractive theory is that a loss in stem cell number and/or activity over time causes this decline. In accordance with this theory, aging phenotypes have been described for stem cells of multiple tissues, including those of the hematopoietic system, intestine, muscle, brain, skin and germline. Here, we discuss recent advances in our understanding of why adult stem cells age and how this aging impacts diseases and lifespan. With this increased understanding, it is feasible to design and test interventions that delay stem cell aging and improve both health and lifespan. PMID:26732838

  2. Accelerated aging effects on surface hardness and roughness of lingual retainer adhesives.

    PubMed

    Ramoglu, Sabri Ilhan; Usumez, Serdar; Buyukyilmaz, Tamer

    2008-01-01

    To test the null hypothesis that accelerated aging has no effect on the surface microhardness and roughness of two light-cured lingual retainer adhesives. Ten samples of light-cured materials, Transbond Lingual Retainer (3M Unitek) and Light Cure Retainer (Reliance) were cured with a halogen light for 40 seconds. Vickers hardness and surface roughness were measured before and after accelerated aging of 300 hours in a weathering tester. Differences between mean values were analyzed for statistical significance using a t-test. The level of statistical significance was set at P < .05. The mean Vickers hardness of Transbond Lingual Retainer was 62.8 +/- 3.5 and 79.6 +/- 4.9 before and after aging, respectively. The mean Vickers hardness of Light Cure Retainer was 40.3 +/- 2.6 and 58.3 +/- 4.3 before and after aging, respectively. Differences in both groups were statistically significant (P < .001). Following aging, mean surface roughness was changed from 0.039 microm to 0.121 microm and from 0.021 microm to 0.031 microm for Transbond Lingual Retainer and Light Cure Retainer, respectively. The roughening of Transbond Lingual Retainer with aging was statistically significant (P < .05), while the change in the surface roughness of Light Cure Retainer was not (P > .05). Accelerated aging significantly increased the surface microhardness of both light-cured retainer adhesives tested. It also significantly increased the surface roughness of the Transbond Lingual Retainer.

  3. Solder joint aging characteristics from the MC2918 firing set of a B61 accelerated aging unit (AAU)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Vianco, P.T.; Rejent, J.A.

    1997-10-01

    The B61 accelerated aging unit (AAU) provided a unique opportunity to document the effects of a controlled, long-term thermal cycling environment on the aging of materials used in the device. This experiment was of particular interest to solder technologists because thermal cycling environments are a predominant source of solder joint failures in electronic assemblies. Observations of through hole solder joints in the MC2918 Firing Set from the B61 AAU did not reveal signs of catastrophic failure. Quantitative analyses of the microstructural metrics of intermetallic compound layer thickness and Pb-rich phase particle distributions indicated solder joint aging that was commensurate withmore » the accelerated aging environment. The effects of stress-enhanced coarsening of the Pb-rich phase were also documented.« less

  4. Towards Accelerated Aging Methodologies and Health Management of Power MOSFETs (Technical Brief)

    NASA Technical Reports Server (NTRS)

    Celaya, Jose R.; Patil, Nishad; Saha, Sankalita; Wysocki, Phil; Goebel, Kai

    2009-01-01

    Understanding aging mechanisms of electronic components is of extreme importance in the aerospace domain where they are part of numerous critical subsystems including avionics. In particular, power MOSFETs are of special interest as they are involved in high voltage switching circuits such as drivers for electrical motors. With increased use of electronics in aircraft control, it becomes more important to understand the degradation of these components in aircraft specific environments. In this paper, we present an accelerated aging methodology for power MOSFETs that subject the devices to indirect thermal overstress during high voltage switching. During this accelerated aging process, two major modes of failure were observed - latch-up and die attach degradation. In this paper we present the details of our aging methodology along with details of experiments and analysis of the results.

  5. Accelerated aging of EPDM and butyl elastomers

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wilson, M.H.

    1996-06-01

    This study was composed of three parts: a post cure study to optimize final properties of an ethylene-propylene-diene (EPDM) formulation, an accelerated aging study to compare the stress relaxation behavior of a butyl and an EPDM elastomer under compression, and a cursory evaluation of a new 70 Shore A EPDM. The optimum postcure for the EPDM was found to be 2 to 4 hours at 182{degrees}C in a vacuum. The EPDM was also shown to have superior aging characteristics compared to the butyl and is recommended for use instead of the butyl material. The physical properties for new 70 Shoremore » A EPDM are satisfactory, and the stress relaxation behavior was only slightly inferior to the other EPDM.« less

  6. Mitochondrial oxidative stress caused by Sod2 deficiency promotes cellular senescence and aging phenotypes in the skin

    PubMed Central

    Velarde, Michael C.; Flynn, James M.; Day, Nicholas U.; Melov, Simon; Campisi, Judith

    2012-01-01

    Cellular senescence arrests the proliferation of mammalian cells at risk for neoplastic transformation, and is also associated with aging. However, the factors that cause cellular senescence during aging are unclear. Excessive reactive oxygen species (ROS) have been shown to cause cellular senescence in culture, and accumulated molecular damage due to mitochondrial ROS has long been thought to drive aging phenotypes in vivo. Here, we test the hypothesis that mitochondrial oxidative stress can promote cellular senescence in vivo and contribute to aging phenotypes in vivo, specifically in the skin. We show that the number of senescent cells, as well as impaired mitochondrial (complex II) activity increase in naturally aged mouse skin. Using a mouse model of genetic Sod2 deficiency, we show that failure to express this important mitochondrial anti-oxidant enzyme also impairs mitochondrial complex II activity, causes nuclear DNA damage, and induces cellular senescence but not apoptosis in the epidermis. Sod2 deficiency also reduced the number of cells and thickness of the epidermis, while increasing terminal differentiation. Our results support the idea that mitochondrial oxidative stress and cellular senescence contribute to aging skin phenotypes in vivo. PMID:22278880

  7. Maternal age generates phenotypic variation in C. elegans

    PubMed Central

    Hidalgo-Carcedo, Cristina; Lehner, Ben

    2017-01-01

    Genetically identical individuals growing in the same environment often show substantial phenotypic variation within populations of organisms as diverse as bacteria1, nematodes2, rodents3 and humans4. With some exceptions5, the causes are poorly understood. We show here that isogenic Caenorhabditis elegans nematodes vary in their size at hatching, speed of development, growth rate, starvation resistance, fecundity, and also in the rate of development of their germline relative to that of somatic tissues. Surprisingly, we show that the primary cause of this variation is the age of an individual’s mother, with young mothers producing progeny impaired for many traits. We identify age-dependent changes in maternal provisioning of a lipoprotein complex (vitellogenin) to embryos as the molecular mechanism underlying variation in multiple traits throughout the life of an animal. The production of sub-optimal progeny by young mothers likely reflects a trade-off between the competing fitness traits of a short generation time and progeny survival and fecundity. PMID:29186117

  8. When stem cells grow old: phenotypes and mechanisms of stem cell aging.

    PubMed

    Schultz, Michael B; Sinclair, David A

    2016-01-01

    All multicellular organisms undergo a decline in tissue and organ function as they age. An attractive theory is that a loss in stem cell number and/or activity over time causes this decline. In accordance with this theory, aging phenotypes have been described for stem cells of multiple tissues, including those of the hematopoietic system, intestine, muscle, brain, skin and germline. Here, we discuss recent advances in our understanding of why adult stem cells age and how this aging impacts diseases and lifespan. With this increased understanding, it is feasible to design and test interventions that delay stem cell aging and improve both health and lifespan. © 2016. Published by The Company of Biologists Ltd.

  9. Accelerated Aging Test for Plastic Scintillator Gamma Ray Detectors

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kouzes, Richard T.

    Polyvinyl toluene (PVT) and polystyrene (PS), collectively referred to as “plastic scintillator,” are synthetic polymer materials used to detect gamma radiation, and are commonly used in instrumentation. Recent studies have revealed that plastic scintillator undergoes an environmentally related material degradation that adversely affects performance under certain conditions and histories. A significant decrease in gamma ray sensitivity has been seen in some detectors in systems as they age. The degradation of sensitivity of plastic scintillator over time is due to a variety of factors, and the term “aging” is used to encompass all factors. Some plastic scintillator samples show no agingmore » effects (no significant change in sensitivity over more than 10 years), while others show severe aging (significant change in sensitivity in less than 5 years). Aging effects arise from weather (variations in heat and humidity), chemical exposure, mechanical stress, light exposure, and loss of volatile components. The damage produced by these various causes can be cumulative, causing observable damage to increase over time. Damage may be reversible up to some point, but becomes permanent under some conditions. It has been demonstrated that exposure of plastic scintillator in an environmental chamber to 30 days of high temperature and humidity (90% relative humidity and 55°C) followed by a single cycle to cold temperature (-30°C) will produce severe fogging in all PVT samples. This thermal cycle will be referred to as the “Accelerated Aging Test.” This document describes the procedure for performing this Accelerated Aging Test.« less

  10. Evaluation of hardness and colour change of soft liners after accelerated ageing.

    PubMed

    Mancuso, Daniela Nardi; Goiato, Marcelo Coelho; Zuccolotti, Bruna Carolina Rossatti; Moreno, Amália; dos Santos, Daniela Micheline

    2009-07-01

    Soft liners have been developed to offer comfort to denture wearers. However, this comfort is compromised when there is a change in the properties of the material, causing colour change, solubility, absorption and hardening. These characteristics can compromise the longevity of soft liners. The aim of this in vitro study was to investigate the effect of ageing on both the hardness and colour change of two soft liners following accelerated ageing. Two denture liners, one resin based (Trusoft, Bosworth, Illinois, USA) and one silicone based (Ufi Gel P, Voco GMBH, Cuxhaven, Germany), were tested in this study for both hardness (using the Shore A scale) and colour change (using the CIE L*a*b* colour scale), initially and after 1008 hours (6 weeks) of accelerated ageing. Statistical analysis was performed using the unpaired t-test with the Welch correction. These indicated that both materials increased in hardness and underwent colour change after accelerated ageing. The initial hardness of Trusoft was far lower than that of Ufi Gel P (18.2 Shore A units vs 34.8 Shore A units). However, for Trusoft the changes for both hardness (from 18.2 to 52.1 Shore A units) and colour change (16.85 on the CIE L*a*b* colour scale) were greater than those for Ufi Gel P, for which hardness changed from 34.8 to 36.5 Shore A units and the colour change was 5.19 on the CIE L*a*b* colour scale. Ufi Gel P underwent less hardness and colour change after accelerated ageing than Trusoft. On the other hand, the use of Trusoft may be preferable in cases where initial softness is a major consideration, such as when relining an immediate denture after implant surgery.

  11. Parasite infection accelerates age polyethism in young honey bees

    PubMed Central

    Lecocq, Antoine; Jensen, Annette Bruun; Kryger, Per; Nieh, James C.

    2016-01-01

    Honey bees (Apis mellifera) are important pollinators and their health is threatened worldwide by persistent exposure to a wide range of factors including pesticides, poor nutrition, and pathogens. Nosema ceranae is a ubiquitous microsporidian associated with high colony mortality. We used lab micro-colonies of honey bees and video analyses to track the effects of N. ceranae infection and exposure on a range of individual and social behaviours in young adult bees. We provide detailed data showing that N. ceranae infection significantly accelerated the age polyethism of young bees, causing them to exhibit behaviours typical of older bees. Bees with high N. ceranae spore counts had significantly increased walking rates and decreased attraction to queen mandibular pheromone. Infected bees also exhibited higher rates of trophallaxis (food exchange), potentially reflecting parasite manipulation to increase colony infection. However, reduction in queen contacts could help bees limit the spread of infection. Such accelerated age polyethism may provide a form of behavioural immunity, particularly if it is elicited by a wide variety of pathogens. PMID:26912310

  12. Parasite infection accelerates age polyethism in young honey bees.

    PubMed

    Lecocq, Antoine; Jensen, Annette Bruun; Kryger, Per; Nieh, James C

    2016-02-25

    Honey bees (Apis mellifera) are important pollinators and their health is threatened worldwide by persistent exposure to a wide range of factors including pesticides, poor nutrition, and pathogens. Nosema ceranae is a ubiquitous microsporidian associated with high colony mortality. We used lab micro-colonies of honey bees and video analyses to track the effects of N. ceranae infection and exposure on a range of individual and social behaviours in young adult bees. We provide detailed data showing that N. ceranae infection significantly accelerated the age polyethism of young bees, causing them to exhibit behaviours typical of older bees. Bees with high N. ceranae spore counts had significantly increased walking rates and decreased attraction to queen mandibular pheromone. Infected bees also exhibited higher rates of trophallaxis (food exchange), potentially reflecting parasite manipulation to increase colony infection. However, reduction in queen contacts could help bees limit the spread of infection. Such accelerated age polyethism may provide a form of behavioural immunity, particularly if it is elicited by a wide variety of pathogens.

  13. Lipid-laden cells differentially distributed in the aging brain are functionally active and correspond to distinct phenotypes.

    PubMed

    Shimabukuro, Marilia Kimie; Langhi, Larissa Gutman Paranhos; Cordeiro, Ingrid; Brito, José M; Batista, Claudia Maria de Castro; Mattson, Mark P; Mello Coelho, Valeria de

    2016-03-31

    We characterized cerebral Oil Red O-positive lipid-laden cells (LLC) of aging mice evaluating their distribution, morphology, density, functional activities and inflammatory phenotype. We identified LLC in meningeal, cortical and neurogenic brain regions. The density of cerebral LLC increased with age. LLC presenting small lipid droplets were visualized adjacent to blood vessels or deeper in the brain cortical and striatal parenchyma of aging mice. LLC with larger droplets were asymmetrically distributed in the cerebral ventricle walls, mainly located in the lateral wall. We also found that LLC in the subventricular region co-expressed beclin-1 or LC3, markers for autophagosome or autophagolysosome formation, and perilipin (PLIN), a lipid droplet-associated protein, suggesting lipophagic activity. Some cerebral LLC exhibited β galactosidase activity indicating a senescence phenotype. Moreover, we detected production of the pro-inflammatory cytokine TNF-α in cortical PLIN(+) LLC. Some cortical NeuN(+) neurons, GFAP(+) glia limitans astrocytes, Iba-1(+) microglia and S100β(+) ependymal cells expressed PLIN in the aging brain. Our findings suggest that cerebral LLC exhibit distinct cellular phenotypes and may participate in the age-associated neuroinflammatory processes.

  14. Lipid-laden cells differentially distributed in the aging brain are functionally active and correspond to distinct phenotypes

    PubMed Central

    Shimabukuro, Marilia Kimie; Langhi, Larissa Gutman Paranhos; Cordeiro, Ingrid; Brito, José M.; Batista, Claudia Maria de Castro; Mattson, Mark P.; de Mello Coelho, Valeria

    2016-01-01

    We characterized cerebral Oil Red O-positive lipid-laden cells (LLC) of aging mice evaluating their distribution, morphology, density, functional activities and inflammatory phenotype. We identified LLC in meningeal, cortical and neurogenic brain regions. The density of cerebral LLC increased with age. LLC presenting small lipid droplets were visualized adjacent to blood vessels or deeper in the brain cortical and striatal parenchyma of aging mice. LLC with larger droplets were asymmetrically distributed in the cerebral ventricle walls, mainly located in the lateral wall. We also found that LLC in the subventricular region co-expressed beclin-1 or LC3, markers for autophagosome or autophagolysosome formation, and perilipin (PLIN), a lipid droplet-associated protein, suggesting lipophagic activity. Some cerebral LLC exhibited β galactosidase activity indicating a senescence phenotype. Moreover, we detected production of the pro-inflammatory cytokine TNF-α in cortical PLIN+ LLC. Some cortical NeuN+ neurons, GFAP+ glia limitans astrocytes, Iba-1+ microglia and S100β+ ependymal cells expressed PLIN in the aging brain. Our findings suggest that cerebral LLC exhibit distinct cellular phenotypes and may participate in the age-associated neuroinflammatory processes. PMID:27029648

  15. Accelerated Gray and White Matter Deterioration With Age in Schizophrenia.

    PubMed

    Cropley, Vanessa L; Klauser, Paul; Lenroot, Rhoshel K; Bruggemann, Jason; Sundram, Suresh; Bousman, Chad; Pereira, Avril; Di Biase, Maria A; Weickert, Thomas W; Weickert, Cynthia Shannon; Pantelis, Christos; Zalesky, Andrew

    2017-03-01

    Although brain changes in schizophrenia have been proposed to mirror those found with advancing age, the trajectory of gray matter and white matter changes during the disease course remains unclear. The authors sought to measure whether these changes in individuals with schizophrenia remain stable, are accelerated, or are diminished with age. Gray matter volume and fractional anisotropy were mapped in 326 individuals diagnosed with schizophrenia or schizoaffective disorder and in 197 healthy comparison subjects aged 20-65 years. Polynomial regression was used to model the influence of age on gray matter volume and fractional anisotropy at a whole-brain and voxel level. Between-group differences in gray matter volume and fractional anisotropy were regionally localized across the lifespan using permutation testing and cluster-based inference. Significant loss of gray matter volume was evident in schizophrenia, progressively worsening with age to a maximal loss of 8% in the seventh decade of life. The inferred rate of gray matter volume loss was significantly accelerated in schizophrenia up to middle age and plateaued thereafter. In contrast, significant reductions in fractional anisotropy emerged in schizophrenia only after age 35, and the rate of fractional anisotropy deterioration with age was constant and best modeled with a straight line. The slope of this line was 60% steeper in schizophrenia relative to comparison subjects, indicating a significantly faster rate of white matter deterioration with age. The rates of reduction of gray matter volume and fractional anisotropy were significantly faster in males than in females, but an interaction between sex and diagnosis was not evident. The findings suggest that schizophrenia is characterized by an initial, rapid rate of gray matter loss that slows in middle life, followed by the emergence of a deficit in white matter that progressively worsens with age at a constant rate.

  16. Accelerated aging in schizophrenia patients: the potential role of oxidative stress.

    PubMed

    Okusaga, Olaoluwa O

    2014-08-01

    Several lines of evidence suggest that schizophrenia, a severe mental illness characterized by delusions, hallucinations and thought disorder is associated with accelerated aging. The free radical (oxidative stress) theory of aging assumes that aging occurs as a result of damage to cell constituents and connective tissues by free radicals arising from oxygen-associated reactions. Schizophrenia has been associated with oxidative stress and chronic inflammation, both of which also appear to reciprocally induce each other in a positive feedback manner. The buildup of damaged macromolecules due to increased oxidative stress and failure of protein repair and maintenance systems is an indicator of aging both at the cellular and organismal level. When compared with age-matched healthy controls, schizophrenia patients have higher levels of markers of oxidative cellular damage such as protein carbonyls, products of lipid peroxidation and DNA hydroxylation. Potential confounders such as antipsychotic medication, smoking, socio-economic status and unhealthy lifestyle make it impossible to solely attribute the earlier onset of aging-related changes or oxidative stress to having a diagnosis of schizophrenia. Regardless of whether oxidative stress can be attributed solely to a diagnosis of schizophrenia or whether it is due to other factors associated with schizophrenia, the available evidence is in support of increased oxidative stress-induced cellular damage of macromolecules which may play a role in the phenomenon of accelerated aging presumed to be associated with schizophrenia.

  17. Associations of Age and Sex with Marfan Phenotype: The NHLBI GenTAC Registry

    PubMed Central

    Roman, Mary J.; Devereux, Richard B.; Preiss, Liliana R.; Asch, Federico M.; Eagle, Kim A.; Holmes, Kathryn W.; LeMaire, Scott A.; Maslen, Cheryl L.; Milewicz, Dianna M.; Morris, Shaine A.; Prakash, Siddharth K.; Pyeritz, Reed E.; Ravekes, William J.; Shohet, Ralph V.; Song, Howard K.; Weinsaft, Jonathan W.

    2017-01-01

    Background The associations of age and sex with phenotypic features of Marfan syndrome have not been systematically examined in a large cohort of both children and adults. Methods and Results We evaluated 789 Marfan patients enrolled in the NHLBI GenTAC Registry (53% male; mean age 31 [range: 1–86 years]). Females aged≥15 and males aged≥16 years were considered adults based on average age of skeletal maturity. Adults (n=606) were more likely than children (n=183) likely to have spontaneous pneumothorax, scoliosis, and striae, but were comparable in revised Ghent systemic score, ectopia lentis, and most phenotypic features, including prevalence of aortic root dilatation. Prophylactic aortic root replacement and mitral valve surgery were rare during childhood vs. adulthood (2 vs. 35% and 1 vs. 9%, respectively, both p<0.0001). Adult males were more likely than females to have aortic root dilatation (92 vs. 84%), aortic regurgitation (55 vs. 36%) and to have undergone prophylactic aortic root replacement (47 vs. 24%), all p<0.001. Prevalence of prior aortic dissection tended to be higher in males than females (25 vs. 18%, p=0.06); 44% of dissections were type B. Type B dissection was strongly associated with previous prophylactic aortic root replacement. Conclusions Pulmonary, skeletal and aortic complications, but not other phenotypic features, are more prevalent in adults than children in Marfan syndrome. Aortic aneurysms and prophylactic aortic surgery are more common in men. Aortic dissection, commonly type B, occurs in an appreciable proportion of Marfan patients, especially in men and following previous prophylactic aortic root replacement. PMID:28600386

  18. Correlation between mechanical and chemical degradation after outdoor and accelerated laboratory aging for multilayer photovoltaic backsheets

    NASA Astrophysics Data System (ADS)

    Lin, Chiao-Chi; Lyu, Yadong; Yu, Li-Chieh; Gu, Xiaohong

    2016-09-01

    Channel cracking fragmentation testing and attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy were utilized to study mechanical and chemical degradation of a multilayered backsheet after outdoor and accelerated laboratory aging. A model sample of commercial PPE backsheet, namely polyethylene terephthalate/polyethylene terephthalate/ethylene vinyl acetate (PET/PET/EVA) was investigated. Outdoor aging was performed in Gaithersburg, Maryland, USA for up to 510 days, and complementary accelerated laboratory aging was conducted on the NIST (National Institute of Standards and Technology) SPHERE (Simulated Photodegradation via High Energy Radiant Exposure). Fracture energy, mode I stress intensity factor and film strength were analyzed using an analytical model based on channel cracking fragmentation testing results. The correlation between mechanical and chemical degradation was discussed for both outdoor and accelerated laboratory aging. The results of this work provide preliminary understanding on failure mechanism of backsheets after weathering, laying the groundwork for linking outdoor and indoor accelerated laboratory testing for multilayer photovoltaic backsheets.

  19. Idh2 deficiency accelerates renal dysfunction in aged mice.

    PubMed

    Lee, Su Jeong; Cha, Hanvit; Lee, Seoyoon; Kim, Hyunjin; Ku, Hyeong Jun; Kim, Sung Hwan; Park, Jung Hyun; Lee, Jin Hyup; Park, Kwon Moo; Park, Jeen-Woo

    2017-11-04

    The free radical or oxidative stress theory of aging postulates that senescence is due to an accumulation of cellular oxidative damage, caused largely by reactive oxygen species (ROS) that are produced as by-products of normal metabolic processes in mitochondria. The oxidative stress may arise as a result of either increased ROS production or decreased ability to detoxify ROS. The availability of the mitochondrial NADPH pool is critical for the maintenance of the mitochondrial antioxidant system. The major enzyme responsible for generating mitochondrial NADPH is mitochondrial NADP + -dependent isocitrate dehydrogenase (IDH2). Depletion of IDH2 in mice (idh2 -/- ) shortens life span and accelerates the degeneration of multiple age-sensitive traits, such as hair grayness, skin pathology, and eye pathology. Among the various internal organs tested in this study, IDH2 depletion-induced acceleration of senescence was uniquely observed in the kidney. Renal function and structure were greatly deteriorated in 24-month-old idh2 -/- mice compared with wild-type. In addition, disruption of redox status, which promotes oxidative damage and apoptosis, was more pronounced in idh2 -/- mice. These data support a significant role for increased oxidative stress as a result of compromised mitochondrial antioxidant defenses in modulating life span in mice, and thus support the oxidative stress theory of aging. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. The evolution of human phenotypic plasticity: age and nutritional status at maturity.

    PubMed

    Gage, Timothy B

    2003-08-01

    Several evolutionary optimal models of human plasticity in age and nutritional status at reproductive maturation are proposed and their dynamics examined. These models differ from previously published models because fertility is not assumed to be a function of body size or nutritional status. Further, the models are based on explicitly human demographic patterns, that is, model human life-tables, model human fertility tables, and, a nutrient flow-based model of maternal nutritional status. Infant survival (instead of fertility as in previous models) is assumed to be a function of maternal nutritional status. Two basic models are examined. In the first the cost of reproduction is assumed to be a constant proportion of total nutrient flow. In the second the cost of reproduction is constant for each birth. The constant proportion model predicts a negative slope of age and nutritional status at maturation. The constant cost per birth model predicts a positive slope of age and nutritional status at maturation. Either model can account for the secular decline in menarche observed over the last several centuries in Europe. A search of the growth literature failed to find definitive empirical documentation of human phenotypic plasticity in age and nutritional status at maturation. Most research strategies confound genetics with phenotypic plasticity. The one study that reports secular trends suggests a marginally insignificant, but positive slope. This view tends to support the constant cost per birth model.

  1. Accelerating glioblastoma drug discovery: Convergence of patient-derived models, genome editing and phenotypic screening.

    PubMed

    O'Duibhir, Eoghan; Carragher, Neil O; Pollard, Steven M

    2017-04-01

    Patients diagnosed with glioblastoma (GBM) continue to face a bleak prognosis. It is critical that new effective therapeutic strategies are developed. GBM stem cells have molecular hallmarks of neural stem and progenitor cells and it is possible to propagate both non-transformed normal neural stem cells and GBM stem cells, in defined, feeder-free, adherent culture. These primary stem cell lines provide an experimental model that is ideally suited to cell-based drug discovery or genetic screens in order to identify tumour-specific vulnerabilities. For many solid tumours, including GBM, the genetic disruptions that drive tumour initiation and growth have now been catalogued. CRISPR/Cas-based genome editing technologies have recently emerged, transforming our ability to functionally annotate the human genome. Genome editing opens prospects for engineering precise genetic changes in normal and GBM-derived neural stem cells, which will provide more defined and reliable genetic models, with critical matched pairs of isogenic cell lines. Generation of more complex alleles such as knock in tags or fluorescent reporters is also now possible. These new cellular models can be deployed in cell-based phenotypic drug discovery (PDD). Here we discuss the convergence of these advanced technologies (iPS cells, neural stem cell culture, genome editing and high content phenotypic screening) and how they herald a new era in human cellular genetics that should have a major impact in accelerating glioblastoma drug discovery. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  2. US Particle Accelerators at Age 50.

    ERIC Educational Resources Information Center

    Wilson, R. R.

    1981-01-01

    Reviews the development of accelerators over the past 50 years. Topics include: types of accelerators, including cyclotrons; sociology of accelerators (motivation, financing, construction, and use); impact of war; national laboratories; funding; applications; future projects; foreign projects; and international collaborations. (JN)

  3. Lifetime stress accelerates epigenetic aging in an urban, African American cohort: relevance of glucocorticoid signaling.

    PubMed

    Zannas, Anthony S; Arloth, Janine; Carrillo-Roa, Tania; Iurato, Stella; Röh, Simone; Ressler, Kerry J; Nemeroff, Charles B; Smith, Alicia K; Bradley, Bekh; Heim, Christine; Menke, Andreas; Lange, Jennifer F; Brückl, Tanja; Ising, Marcus; Wray, Naomi R; Erhardt, Angelika; Binder, Elisabeth B; Mehta, Divya

    2015-12-17

    Chronic psychological stress is associated with accelerated aging and increased risk for aging-related diseases, but the underlying molecular mechanisms are unclear. We examined the effect of lifetime stressors on a DNA methylation-based age predictor, epigenetic clock. After controlling for blood cell-type composition and lifestyle parameters, cumulative lifetime stress, but not childhood maltreatment or current stress alone, predicted accelerated epigenetic aging in an urban, African American cohort (n = 392). This effect was primarily driven by personal life stressors, was more pronounced with advancing age, and was blunted in individuals with higher childhood abuse exposure. Hypothesizing that these epigenetic effects could be mediated by glucocorticoid signaling, we found that a high number (n = 85) of epigenetic clock CpG sites were located within glucocorticoid response elements. We further examined the functional effects of glucocorticoids on epigenetic clock CpGs in an independent sample with genome-wide DNA methylation (n = 124) and gene expression data (n = 297) before and after exposure to the glucocorticoid receptor agonist dexamethasone. Dexamethasone induced dynamic changes in methylation in 31.2 % (110/353) of these CpGs and transcription in 81.7 % (139/170) of genes neighboring epigenetic clock CpGs. Disease enrichment analysis of these dexamethasone-regulated genes showed enriched association for aging-related diseases, including coronary artery disease, arteriosclerosis, and leukemias. Cumulative lifetime stress may accelerate epigenetic aging, an effect that could be driven by glucocorticoid-induced epigenetic changes. These findings contribute to our understanding of mechanisms linking chronic stress with accelerated aging and heightened disease risk.

  4. A longitudinal study of DNA methylation as a potential mediator of age-related diabetes risk.

    PubMed

    Grant, Crystal D; Jafari, Nadereh; Hou, Lifang; Li, Yun; Stewart, James D; Zhang, Guosheng; Lamichhane, Archana; Manson, JoAnn E; Baccarelli, Andrea A; Whitsel, Eric A; Conneely, Karen N

    2017-12-01

    DNA methylation (DNAm) has been found to show robust and widespread age-related changes across the genome. DNAm profiles from whole blood can be used to predict human aging rates with great accuracy. We sought to test whether DNAm-based predictions of age are related to phenotypes associated with type 2 diabetes (T2D), with the goal of identifying risk factors potentially mediated by DNAm. Our participants were 43 women enrolled in the Women's Health Initiative. We obtained methylation data via the Illumina 450K Methylation array on whole blood samples from participants at three timepoints, covering on average 16 years per participant. We employed the method and software of Horvath, which uses DNAm at 353 CpGs to form a DNAm-based estimate of chronological age. We then calculated the epigenetic age acceleration, or Δ age , at each timepoint. We fit linear mixed models to characterize how Δ age contributed to a longitudinal model of aging and diabetes-related phenotypes and risk factors. For most participants, Δ age remained constant, indicating that age acceleration is generally stable over time. We found that Δ age associated with body mass index (p = 0.0012), waist circumference (p = 0.033), and fasting glucose (p = 0.0073), with the relationship with BMI maintaining significance after correction for multiple testing. Replication in a larger cohort of 157 WHI participants spanning 3 years was unsuccessful, possibly due to the shorter time frame covered. Our results suggest that DNAm has the potential to act as a mediator between aging and diabetes-related phenotypes, or alternatively, may serve as a biomarker of these phenotypes.

  5. Aging accelerates memory extinction and impairs memory restoration in Drosophila.

    PubMed

    Chen, Nannan; Guo, Aike; Li, Yan

    2015-05-15

    Age-related memory impairment (AMI) is a phenomenon observed from invertebrates to human. Memory extinction is proposed to be an active inhibitory modification of memory, however, whether extinction is affected in aging animals remains to be elucidated. Employing a modified paradigm for studying memory extinction in fruit flies, we found that only the stable, but not the labile memory component was suppressed by extinction, thus effectively resulting in higher memory loss in aging flies. Strikingly, young flies were able to fully restore the stable memory component 3 h post extinction, while aging flies failed to do so. In conclusion, our findings reveal that both accelerated extinction and impaired restoration contribute to memory impairment in aging animals. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Air Pollution Stress and the Aging Phenotype: The Telomere Connection.

    PubMed

    Martens, Dries S; Nawrot, Tim S

    2016-09-01

    Aging is a complex physiological phenomenon. The question why some subjects grow old while remaining free from disease whereas others prematurely die remains largely unanswered. We focus here on the role of air pollution in biological aging. Hallmarks of aging can be grouped into three main categories: genomic instability, telomere attrition, and epigenetic alterations leading to altered mitochondrial function and cellular senescence. At birth, the initial telomere length of a person is largely determined by environmental factors. Telomere length shortens with each cell division and exposure to air pollution as well as low residential greens space exposure is associated with shorter telomere length. Recent studies show that the estimated effects of particulate air pollution exposure on the telomere mitochondrial axis of aging may play an important role in chronic health effects of air pollution. The exposome encompasses all exposures over an entire life. As telomeres can be considered as the cellular memories of exposure to oxidative stress and inflammation, telomere maintenance may be a proxy for assessing the "exposome". If telomeres are causally related to the aging phenotype and environmental air pollution is an important determinant of telomere length, this might provide new avenues for future preventive strategies.

  7. Adiposity-Related Biochemical Phenotype in Senescence-Accelerated Mouse Prone 6 (SAMP6)

    PubMed Central

    Niimi, Kimie; Takahashi, Eiki; Itakura, Chitoshi

    2009-01-01

    Senescence-accelerated mouse prone 6 (SAMP6) is a model of senile osteoporosis. From 10 to 22 wk of age, SAMP6 mice were heavier than age-matched AKR/J and SAMR1 mice. Body mass indices of 10- and 25-wk-old SAMP6 mice were higher than those of age-matched AKR/J and SAMR1 mice, indicating obesity in the SAMP6 animals. We compared the blood biochemical values among SAMP6, SAMR1, and AKR/J mice to assess whether the SAMP6 strain has abnormal obesity-related parameters. Plasma glucose, triglyceride, insulin, and leptin levels were higher in 10-wk-old SAMP6 mice than in age-matched SAMR1 and AKR/J mice, whereas plasma glucagon and adiponectin levels in 25-wk-old SAMP6 were lower compared with those in age-matched SAMR1 and AKR/J. Total cholesterol levels in SAMR1 and SAMP6 mice at 10 and 25 wk of age were higher than those in AKR/J mice. Hepatic lipid levels were higher in 10- and 25-wk-old SAMP6 mice compared with age-matched AKR/J and SAMR1 animals. These results indicate that SAMP6 mice exhibit obesity and hyperlipidemia, suggesting that the SAMP6 strain is a potential tool for the study of hyperlipidemia. PMID:19887026

  8. Sex-specific phenotypes of hyperthyroidism and hypothyroidism in aged mice.

    PubMed

    Rakov, Helena; Engels, Kathrin; Hönes, Georg Sebastian; Brix, Klaudia; Köhrle, Josef; Moeller, Lars Christian; Zwanziger, Denise; Führer, Dagmar

    2017-12-22

    Sex and age play a role in the prevalence of thyroid dysfunction (TD), but their interrelationship for manifestation of hyper- and hypothyroidism is still not well understood. Using a murine model, we asked whether sex impacts the phenotypes of hyper- and hypothyroidism at two life stages. Hyper- and hypothyroidism were induced by i.p. T4 or MMI/ClO 4 -/LoI treatment over 7 weeks in 12- and 20-months-old female and male C57BL/6N mice. Control animals underwent PBS treatment (n = 7-11 animals/sex/treatment). Animals were investigated for impact of sex on body weight, food and water intake, body temperature, heart rate, behaviour (locomotor activity, motor coordination and strength) and serum thyroid hormone (TH) status. Distinct sex impact was found in eu- and hyperthyroid mice, while phenotypic traits of hypothyroidism were similar in male and female mice. No sex difference was found in TH status of euthyroid mice; however, T4 treatment resulted in twofold higher TT4, FT4 and FT3 serum concentrations in adult and old females compared to male animals. Hyperthyroid females consistently showed higher locomotor activity and better coordination but more impairment of muscle function by TH excess at adult age. Importantly and in contrast to male mice, adult and old hyperthyroid female mice showed increased body weight. Higher body temperature in female mice was confirmed in all age groups. No sex impact was found on heart rate irrespective of TH status in adult and old mice. By comparison of male and female mice with TD at two life stages, we found that sex modulates TH action in an organ- and function-specific manner. Sex differences were more pronounced under hyperthyroid conditions. Importantly, sex-specific differences in features of TD in adult and old mice were not conclusively explained by serum TH status in mice.

  9. Chromatic stability of acrylic resins of artificial eyes submitted to accelerated aging and polishing.

    PubMed

    Goiato, Marcelo Coelho; Santos, Daniela Micheline dos; Souza, Josiene Firmino; Moreno, Amália; Pesqueira, Aldiéris Alves

    2010-12-01

    Esthetics and durability of materials used to fabricate artificial eyes has been an important issue since artificial eyes are essential to restore esthetics and function, protect the remaining tissues and help with patients' psychological therapy. However, these materials are submitted to degrading effects of environmental agents on the physical properties of the acrylic resin. This study assessed the color stability of acrylic resins used to fabricate sclera in three basic shades (N1, N2 and N3) when subjected to accelerated aging, mechanical and chemical polishing. Specimens of each resin were fabricated and submitted to mechanical and chemical polishing. Chromatic analysis was performed before and after accelerated aging through ultraviolet reflection spectrophotometry. All specimens revealed color alteration following polishing and accelerated aging. The resins presented statistically significant chromatic alteration (p<0.01) between the periods of 252 and 1008 h. Both polishing methods presented no significant difference between the values of color derivatives of resins.

  10. Characterization and Accelerated Ageing of UHMWPE Used in Orthopedic Prosthesis by Peroxide

    PubMed Central

    Rocha, Magda; Mansur, Alexandra; Mansur, Herman

    2009-01-01

    Ultra-high molecular weight polyethylene (UHMWPE) has been the most commonly used bearing material in total joint arthroplasty. Wear and oxidation fatigue resistance of UHMWPE are regarded as two important mechanical properties to extend the longevity of knee prostheses. Though accelerated in vitro protocols have been developed to test the relative oxidation resistance of various types of UHMWPE, its mechanism is not accurately understood yet. Thus, in the present study an accelerated ageing of UHMWPE in hydrogen peroxide solution was performed and relative oxidation was extensively characterized by Fourier Transformed Infrared Spectroscopy (FTIR) spectroscopy and the morphological changes were analyzed by Scanning Electron Microscopy (SEM). Different chemical groups of UHMWPE associated with the degradation reaction were monitored for over 120 days in order to evaluate the possible oxidation mechanism(s) which may have occurred. The results have provided strong evidence that the oxidation mechanism is rather complex, and two stages with their own particular first-order kinetics reaction patterns have been clearly identified. Furthermore, hydrogen peroxide has proven to be an efficient oxidative medium to accelerate ageing of UHMWPE.

  11. Accumulation of severely atrophic myofibers marks the acceleration of sarcopenia in slow and fast twitch muscles.

    PubMed

    Rowan, Sharon L; Purves-Smith, Fennigje M; Solbak, Nathan M; Hepple, Russell T

    2011-08-01

    The age-related decline in muscle mass, known as sarcopenia, exhibits a marked acceleration in advanced age. Although many studies have remarked upon the accumulation of very small myofibers, particularly at advanced stages of sarcopenia, the significance of this phenomenon in the acceleration of sarcopenia has never been examined. Furthermore, although mitochondrial dysfunction characterized by a lack of cytochrome oxidase (COX) activity has been implicated in myofiber atrophy in sarcopenia, the contribution of this phenotype to the accumulation of severely atrophied fibers in aged muscles has never been determined. To this end, we examined the fiber size distribution in the slow twitch soleus (Sol) and fast twitch gastrocnemius (Gas) muscles between young adulthood (YA) and senescence (SEN). We also quantified the abundance of COX deficient myocytes and their size attributes to gain insight into the contribution of this phenotype to myofiber atrophy with aging. Our data showed that the progression of muscle atrophy, particularly its striking acceleration between late middle age and SEN, was paralleled by an accumulation of severely atrophic myofibers (≤ 1000 μm(2) in size) in both Sol and Gas. On the other hand, we observed no COX deficient myofibers in Sol, despite nearly 20% of the myofibers being severely atrophic. Similarly, only 0.17 ± 0.06% of all fibers in Gas were COX deficient, and their size was generally larger (2375 ± 319 μm(2)) than the severely atrophied myofibers noted above. Collectively, our results suggest that similar processes likely contribute to the acceleration of sarcopenia in both slow twitch and fast twitch muscles, and that COX deficiency is not a major contributor to this phenomenon. Copyright © 2011 Elsevier Inc. All rights reserved.

  12. The Nutritional Phenotype in the Age of Metabolomics

    PubMed Central

    Zeisel, S. H.; Freake, H. C.; Bauman, D. E.; Bier, D. M.; Burrin, D. G.; German, J. B.; Klein, S.; Marquis, G. S.; Milner, J. A.; Pelto, G. H.; Rasmussen, K. M.

    2008-01-01

    The concept of the nutritional phenotype is proposed as a defined and integrated set of genetic, proteomic, metabolomic, functional, and behavioral factors that, when measured, form the basis for assessment of human nutritional status. The nutritional phenotype integrates the effects of diet on disease/wellness and is the quantitative indication of the paths by which genes and environment exert their effects on health. Advances in technology and in fundamental biological knowledge make it possible to define and measure the nutritional phenotype accurately in a cross section of individuals with various states of health and disease. This growing base of data and knowledge could serve as a resource for all scientific disciplines involved in human health. Nutritional sciences should be a prime mover in making key decisions that include: what environmental inputs (in addition to diet) are needed; what genes/proteins/metabolites should be measured; what end-point phenotypes should be included; and what informatics tools are available to ask nutritionally relevant questions. Nutrition should be the major discipline establishing how the elements of the nutritional phenotype vary as a function of diet. Nutritional sciences should also be instrumental in linking the elements that are responsive to diet with the functional outcomes in organisms that derive from them. As the first step in this initiative, a prioritized list of genomic, proteomic, and metabolomic as well as functional and behavioral measures that defines a practically useful subset of the nutritional phenotype for use in clinical and epidemiological investigations must be developed. From this list, analytic platforms must then be identified that are capable of delivering highly quantitative data on these endpoints. This conceptualization of a nutritional phenotype provides a concrete form and substance to the recognized future of nutritional sciences as a field addressing diet, integrated metabolism, and health

  13. Colour stability of temporary restorations with different thicknesses submitted to artificial accelerated aging.

    PubMed

    Silame, F D J; Tonani, R; Alandia-Roman, C C; Chinelatti, M; Panzeri, H; Pires-de-Souza, F C P

    2013-12-01

    This study evaluated the colour stability of temporary prosthetic restorations with different thicknesses submitted to artificial accelerated aging. The occlusal surfaces of 40 molars were grinded to obtain flat enamel surfaces. Twenty acrylic resin specimens [Polymethyl methacrylate (Duralay) and Bis-methyl acrylate (Luxatemp)] were made with two different thicknesses, 0.5 mm and 1.0 mm. Temporary restorations were fixed on enamel and CIE L*a*b* colour parameters of each specimen were assessed before and after artificial accelerated aging. All groups showed colour alterations above the clinically acceptable limit. Luxatemp showed the lowest colour alteration regardless its thickness and Duralay showed the greatest alteration with 0.5 mm.

  14. Aggrecan Mutations in Nonfamilial Short Stature and Short Stature Without Accelerated Skeletal Maturation.

    PubMed

    Tatsi, Christina; Gkourogianni, Alexandra; Mohnike, Klaus; DeArment, Diana; Witchel, Selma; Andrade, Anenisia C; Markello, Thomas C; Baron, Jeffrey; Nilsson, Ola; Jee, Youn Hee

    2017-08-01

    Aggrecan, a proteoglycan, is an important component of cartilage extracellular matrix, including that of the growth plate. Heterozygous mutations in ACAN , the gene encoding aggrecan, cause autosomal dominant short stature, accelerated skeletal maturation, and joint disease. The inheritance pattern and the presence of bone age equal to or greater than chronological age have been consistent features, serving as diagnostic clues. From family 1, a 6-year-old boy presented with short stature [height standard deviation score (SDS), -1.75] and bone age advanced by 3 years. There was no family history of short stature (height SDS: father, -0.76; mother, 0.7). Exome sequencing followed by Sanger sequencing identified a de novo novel heterozygous frameshift mutation in ACAN (c.6404delC: p.A2135Dfs). From family 2, a 12-year-old boy was evaluated for short stature (height SDS, -3.9). His bone age at the time of genetic evaluation was approximately 1 year less than his chronological age. Family history was consistent with an autosomal dominant inheritance of short stature, with several affected members also showing early-onset osteoarthritis. Exome sequencing, confirmed by Sanger sequencing, identified a novel nonsense mutation in ACAN (c.4852C>T: p.Q1618X), which cosegregated with the phenotype. In conclusion, patients with ACAN mutations may present with nonfamilial short stature and with bone age less than chronological age. These findings expand the known phenotypic spectrum of heterozygous ACAN mutations and indicate that this diagnosis should be considered in children without a family history of short stature and in children without accelerated skeletal maturation.

  15. [Characteristics of the sympathoadrenal system response to psychoemotional stress under hypoxic conditions in aged people with physiological and accelerated aging of the respiratory system].

    PubMed

    Asanov, E O; Os'mak, Ie D; Kuz'mins'ka, L A

    2013-01-01

    The peculiarities of the response of the sympathoadrenal system to psychoemotional and hypoxic stress in healthy young people and in aged people with physiological and accelerated aging of respiratory system were studied. It was shown that in aging a more pronounced response of the sympathoadrenal system to psychoemotional stress. At the same time, elderly people with different types of aging of the respiratory system did not demonstrate a difference in the response of the sympathoadrenal system to psychoemotional stress. Unlike in young people, in aged people, combination of psychoemotional and hypoxic stresses resulted in further activation of the sympathoadrenal system. The reaction of the sympathoadrenal system was more expressed in elderly people with accelerated ageing of the respiratory system.

  16. A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging.

    PubMed

    Patterson, Victoria L; Thompson, Brian S; Cherry, Catherine; Wang, Shao-Bin; Chen, Bo; Hoh, Josephine

    2016-07-14

    Age-related diseases are becoming increasingly prevalent and the burden continues to grow as our population ages. Effective treatments are necessary to lessen the impact of debilitating conditions but remain elusive in many cases. Only by understanding the causes and pathology of diseases associated with aging, can scientists begin to identify potential therapeutic targets and develop strategies for intervention. The most common age-related conditions are neurodegenerative disorders such as Parkinson's disease and blindness. Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Genome wide association studies have previously identified loci that are associated with increased susceptibility to this disease and identified two regions of interest: complement factor H (CFH) and the 10q26 locus, where the age-related maculopathy susceptibility 2 (ARMS2) and high-temperature requirement factor A1 (HtrA1) genes are located. CFH acts as a negative regulator of the alternative pathway (AP) of the complement system while HtrA1 is an extracellular serine protease. ARMS2 is located upstream of HtrA1 in the primate genome, although the gene is absent in mice. To study the effects of these genes, humanized knock-in mouse lines of Cfh and ARMS2, knockouts of Cfh, HtrA1, HtrA2, HtrA3 and HtrA4 as well as a conditional neural deletion of HtrA2 were generated. Of all the genetically engineered mice produced only mice lacking HtrA2, either systemically or in neural tissues, displayed clear phenotypes. In order to examine these mice thoroughly and systematically, an initial phenotyping schedule was established, consisting of a series of tests related to two main diseases of interest: AMD and Parkinson's. Genetically modified mice can be subjected to appropriate experiments to identify phenotypes that may be related to the associated diseases in humans. A phenotyping regimen with a mitochondrial focus is presented here alongside representative results

  17. Computational Approaches to Phenotyping

    PubMed Central

    Lussier, Yves A.; Liu, Yang

    2007-01-01

    The recent completion of the Human Genome Project has made possible a high-throughput “systems approach” for accelerating the elucidation of molecular underpinnings of human diseases, and subsequent derivation of molecular-based strategies to more effectively prevent, diagnose, and treat these diseases. Although altered phenotypes are among the most reliable manifestations of altered gene functions, research using systematic analysis of phenotype relationships to study human biology is still in its infancy. This article focuses on the emerging field of high-throughput phenotyping (HTP) phenomics research, which aims to capitalize on novel high-throughput computation and informatics technology developments to derive genomewide molecular networks of genotype–phenotype associations, or “phenomic associations.” The HTP phenomics research field faces the challenge of technological research and development to generate novel tools in computation and informatics that will allow researchers to amass, access, integrate, organize, and manage phenotypic databases across species and enable genomewide analysis to associate phenotypic information with genomic data at different scales of biology. Key state-of-the-art technological advancements critical for HTP phenomics research are covered in this review. In particular, we highlight the power of computational approaches to conduct large-scale phenomics studies. PMID:17202287

  18. Obesity-induced oxidative stress, accelerated functional decline with age and increased mortality in mice.

    PubMed

    Zhang, Yiqiang; Fischer, Kathleen E; Soto, Vanessa; Liu, Yuhong; Sosnowska, Danuta; Richardson, Arlan; Salmon, Adam B

    2015-06-15

    Obesity is a serious chronic disease that increases the risk of numerous co-morbidities including metabolic syndrome, cardiovascular disease and cancer as well as increases risk of mortality, leading some to suggest this condition represents accelerated aging. Obesity is associated with significant increases in oxidative stress in vivo and, despite the well-explored relationship between oxidative stress and aging, the role this plays in the increased mortality of obese subjects remains an unanswered question. Here, we addressed this by undertaking a comprehensive, longitudinal study of a group of high fat-fed obese mice and assessed both their changes in oxidative stress and in their performance in physiological assays known to decline with aging. In female C57BL/6J mice fed a high-fat diet starting in adulthood, mortality was significantly increased as was oxidative damage in vivo. High fat-feeding significantly accelerated the decline in performance in several assays, including activity, gait, and rotarod. However, we also found that obesity had little effect on other markers of function and actually improved performance in grip strength, a marker of muscular function. Together, this first comprehensive assessment of longitudinal, functional changes in high fat-fed mice suggests that obesity may induce segmental acceleration of some of the aging process. Published by Elsevier Inc.

  19. Obesity-induced oxidative stress, accelerated functional decline with age and increased mortality in mice

    PubMed Central

    Zhang, Yiqiang; Fischer, Kathleen E.; Soto, Vanessa; Liu, Yuhong; Sosnowska, Danuta; Richardson, Arlan; Salmon, Adam B.

    2015-01-01

    Obesity is a serious chronic disease that increases the risk of numerous co-morbidities including metabolic syndrome, cardiovascular disease and cancer as well as increases risk of mortality leading some to suggest this represents accelerated aging. Obesity is associated with significant increases in oxidative stress in vivo and, despite the well-explored relationship between oxidative stress and aging, the role this plays in the increased mortality of obese subjects remains an unanswered question. Here, we addressed this by undertaking a comprehensive, longitudinal study of a group of high fat-fed obese mice and assessed both their changes in oxidative stress and in their performance in physiological assays known to decline with aging. In female C57BL/6J mice fed a high-fat diet starting in adulthood, mortality was significantly increased in high fat-fed mice as was oxidative damage in vivo. High fat-feeding significantly accelerated the decline in performance in several assays, including activity, gait, and rotarod. However, we also found that obesity had little effect on other markers and actually improved performance in grip strength, a marker of muscular function. Together, this first comprehensive assessment of longitudinal functional changes in high fat-fed mice suggests that obesity may induce segmental acceleration of some of the aging process. PMID:25558793

  20. Color Stability of CAD/CAM Fabricated Inlays after Accelerated Artificial Aging.

    PubMed

    Karaokutan, Isil; Yilmaz Savas, Tuba; Aykent, Filiz; Ozdere, Eda

    2016-08-01

    To investigate the influence of accelerated artificial aging on the color stability of three different inlay restorations produced with a CAD/CAM system. Thirty non-carious human mandibular molar teeth were used. The teeth were embedded in autopolymerizing acrylic resin blocks. Standard Class I inlay cavities were prepared, and the teeth were randomly divided into three groups (n = 10) to fabricate inlay restorations: (1) a feldspathic-ceramic group, (2) a resin nano-ceramic group, and (3) a leucite glass-ceramic group. Optical impressions were made with CEREC software, and the restorations were designed and then milled. The inlays were adhesively cemented with a dual-polymerizing resin cement and left in distilled water at room temperature for 1 week. Color measurements were performed with a spectrophotometer before and after accelerated aging in a weathering machine with a total energy of 150 kJ/m(2) . Changes in color (∆E, ∆L, ∆a, ∆b, ∆C) were determined using the CIE L*a*b* system. The results were assessed using a one-way ANOVA and Tukey's HSD test (p = 0.05). The color changes of the materials ranged from 2.1 to 9.29. The highest color change was seen in the resin nano-ceramic material. This change was not clinically acceptable (∆E > 5.5). No significant differences were found in the ∆L and ∆a values of the test groups. Color changes were observed in each evaluated material after accelerated aging. All CAD/CAM inlays became darker in appearance, more saturated, a little reddish, and more yellow. © 2015 by the American College of Prosthodontists.

  1. Mechanical properties experimental investigation of HTPB propellant after thermal accelerated aging

    NASA Astrophysics Data System (ADS)

    Yang, Xiaohong; Sun, Chaoxiang; Zhang, Junfa; Xu, Jinsheng; Tan, Bingdong

    2017-04-01

    To get accurate aging mechanical properties of aged HTPB propellant, the thermal accelerated aging experiment method is utilized and the uniaxial tensile experiments were conducted to obtain the mechanical data of aged HTPB propellants, and the maximum tensile strength, σm, maximum tensile strain, ɛm, and the fracture tensile strain, ɛb, of HTPB propellant with different aging time and various aging temperatures,were obtained, using universal material testing machine. The experimental results show that the σm of HTPB propellant initially increases, subsequently decreases and finally increases with aging time. The ɛm and ɛb generally decrease with increasing aging time, what's more, the decrease rate of both ɛm and ɛb reduce with the aging time. What's more, the postcure effect and oxidation reaction occurred inside HTPB matrix, including the chain degradation reaction and oxidation-induced crosslinking, were discussed to explain the mechanical aging rule of HTPB propellant.

  2. How accelerated biological aging can affect solar reflective polymeric based building materials

    NASA Astrophysics Data System (ADS)

    Ferrari, C.; Santunione, G.; Libbra, A.; Muscio, A.; Sgarbi, E.

    2017-11-01

    Among the main issues concerning building materials, in particular outdoor ones, one can identify the colonization by microorganisms referred to as biological aggression. This can affect not only the aesthetical aspect but also the thermal performance of solar reflective materials. In order to improve the reliability of tests aimed to assess the resistance to biological aggression and contextually reduce the test duration, an accelerated test method has been developed. It is based on a lab reproducible setup where specific and controlled environmental and boundary conditions are imposed to accelerate as much as possible biological growth on building materials. Due to their widespread use, polymeric materials have been selected for the present analysis, in the aim of reaching an advanced bio-aged level in a relatively short time (8 weeks or less) and at the same time comparatively evaluate different materials under a given set of ageing conditions. Surface properties before, during and after ageing have been investigated by surface, microstructural and chemical analyses, as well as by examination of time progressive images to assess bacterial and algal growth rate.

  3. Single-Dose and Fractionated Irradiation Promote Initiation and Progression of Atherosclerosis and Induce an Inflammatory Plaque Phenotype in ApoE{sup -/-} Mice

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hoving, Saske; Heeneman, Sylvia; Gijbels, Marion J.J.

    2008-07-01

    Purpose: Increased risk of atherosclerosis and stroke has been demonstrated in patients receiving radiotherapy for Hodgkin's lymphoma and head-and-neck cancer. We previously showed that 14 Gy to the carotid arteries of hypercholesterolemic ApoE{sup -/-} mice resulted in accelerated development of macrophage-rich, inflammatory atherosclerotic lesions. Here we investigate whether clinically relevant fractionated irradiation schedules and lower single doses also predispose to an inflammatory plaque phenotype. Methods and Materials: ApoE{sup -/-} mice were given 8 or 14 Gy, or 20 x 2.0 Gy in 4 weeks to the neck, and the carotid arteries were subsequently examinated for presence of atherosclerotic lesions, plaquemore » size, and phenotype. Results: At 4 weeks, early atherosclerotic lesions were found in 44% of the mice after single doses of 14 Gy but not in age-matched controls. At 22 to 30 weeks after irradiation there was a twofold increase in the mean number of carotid lesions (8-14 Gy and 20 x 2.0 Gy) and total plaque burden (single doses only), compared with age-matched controls. The majority of lesions seen at 30 to 34 weeks after fractionated irradiation or 14-Gy single doses were granulocyte rich (100% and 63%, respectively), with thrombotic features (90% and 88%), whereas these phenotypes were much less common in age-matched controls or after a single dose of 8 Gy. Conclusions: We showed that fractionated irradiation accelerated the development of atherosclerosis in ApoE{sup -/-} mice and predisposed to the formation of an inflammatory, thrombotic plaque phenotype.« less

  4. Adult-Onset Asthma Becomes the Dominant Phenotype among Women by Age 40 Years. The Longitudinal CARDIA Study

    PubMed Central

    Qualls, Clifford; Schuyler, Mark; Arynchyn, Alexander; Alvarado, Jesse H.; Smith, Lewis J.; Jacobs, David R.

    2013-01-01

    Rationale: Although asthma is usually considered to originate in childhood, adult-onset disease is being increasingly reported. Objectives: To contrast the proportion and natural history of adult-onset versus pediatric-onset asthma in a community-based cohort. We hypothesized that asthma in women is predominantly of adult onset rather than of pediatric onset. Methods: This study used data from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort in the United States over a 25-year period. Adult- and pediatric-onset asthma phenotypes were studied, as defined by age at onset of 18 years or older. Subjects with asthma were categorized by sex, obesity, atopy, smoking, and race by mean age/examination year, using a three-way analysis of covariance model. Natural history of disease was examined using probabilities derived from a Markov chain model. Measurements and Main Results: Asthma of adult onset became the dominant (i.e., exceeded 50%) phenotype in women by age 40 years. The age by which adult-onset asthma became the dominant phenotype was further lowered for obese, nonatopic, ever-smoking, or white women. The prevalence trend with increasing time for adult-onset disease was greater among subjects with nonatopic than atopic asthma among both sexes. Furthermore, adult-onset asthma had remarkable sex-related differences in risk factors. In both sexes, the quiescent state for adult-onset asthma was less frequent and also “less stable” over time than for pediatric-onset asthma. Conclusions: Using a large national cohort, this study challenges the dictum that most asthma in adults originates in childhood. Studies of the differences between pediatric- and adult-onset asthma may provide greater insight into the phenotypic heterogeneity of asthma. PMID:23802814

  5. Does cyclic stress and accelerated ageing influence the wear behavior of highly crosslinked polyethylene?

    PubMed

    Affatato, Saverio; De Mattia, Jonathan Salvatore; Bracco, Pierangiola; Pavoni, Eleonora; Taddei, Paola

    2016-06-01

    First-generation (irradiated and remelted or annealed) and second-generation (irradiated and vitamin E blended or doped) highly crosslinked polyethylenes were introduced in the last decade to solve the problems of wear and osteolysis. In this study, the influence of the Vitamin-E addition on crosslinked polyethylene (XLPE_VE) was evaluated by comparing the in vitro wear behavior of crosslinked polyethylene (XLPE) versus Vitamin-E blended polyethylene XLPE and conventional ultra-high molecular weight polyethylene (STD_PE) acetabular cups, after accelerated ageing according to ASTM F2003-02 (70.0±0.1°C, pure oxygen at 5bar for 14 days). The test was performed using a hip joint simulator run for two millions cycles, under bovine calf serum as lubricant. Mass loss was found to decrease along the series XLPE_VE>STD_PE>XLPE, although no statistically significant differences were found between the mass losses of the three sets of cups. Micro-Raman spectroscopy was used to investigate at a molecular level the morphology changes induced by wear. The spectroscopic analyses showed that the accelerated ageing determined different wear mechanisms and molecular rearrangements during testing with regards to the changes in both the chain orientation and the distribution of the all-trans sequences within the orthorhombic, amorphous and third phases. The results of the present study showed that the addition of vitamin E was not effective to improve the gravimetric wear of PE after accelerated ageing. However, from a molecular point of view, the XLPE_VE acetabular cups tested after accelerated ageing appeared definitely less damaged than the STD_PE ones and comparable to XLPE samples. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. A novel approach on accelerated ageing towards reliability optimization of high concentration photovoltaic cells

    NASA Astrophysics Data System (ADS)

    Tsanakas, John A.; Jaffre, Damien; Sicre, Mathieu; Elouamari, Rachid; Vossier, Alexis; de Salins, Jean-Edouard; Bechou, Laurent; Levrier, Bruno; Perona, Arnaud; Dollet, Alain

    2014-09-01

    This paper presents a preliminary study upon a novel approach proposed for highly accelerated ageing and reliability optimization of high concentrating photovoltaic (HCPV) cells and assemblies. The intended approach aims to overcome several limitations of some current accelerated ageing tests (AAT) adopted up today, proposing the use of an alternative experimental set-up for performing faster and more realistic thermal cycles, under real sun, without the involvement of environmental chamber. The study also includes specific characterization techniques, before and after each AAT sequence, which respectively provide the initial and final diagnosis on the condition of the tested sample. The acquired data from these diagnostic/characterization methods are then used as indices to determine both quantitatively and qualitatively the severity of degradation and, thus, the ageing level for each tested HCPV assembly or cell sample. Ultimate goal of such "initial diagnosis - AAT - final diagnosis" sequences is to provide the basis for a future work on the reliability analysis of the main degradation mechanisms and confident prediction of failure propagation in HCPV cells, by means of acceleration factor (AF) and mean-time-to-failure (MTTF) estimations.

  7. Deficiency of circadian clock protein BMAL1 in mice results in a low bone mass phenotype.

    PubMed

    Samsa, William E; Vasanji, Amit; Midura, Ronald J; Kondratov, Roman V

    2016-03-01

    The circadian clock is an endogenous time keeping system that controls the physiology and behavior of many organisms. The transcription factor Brain and Muscle ARNT-like Protein 1 (BMAL1) is a component of the circadian clock and necessary for clock function. Bmal1(-/-) mice display accelerated aging and many accompanying age associated pathologies. Here, we report that mice deficient for BMAL1 have a low bone mass phenotype that is absent at birth and progressively worsens over their lifespan. Accelerated aging of these mice is associated with the formation of bony bridges occurring across the metaphysis to the epiphysis, resulting in shorter long bones. Using micro-computed tomography we show that Bmal1(-/-) mice have reductions in cortical and trabecular bone volume and other micro-structural parameters and a lower bone mineral density. Histology shows a deficiency of BMAL1 results in a reduced number of active osteoblasts and osteocytes in vivo. Isolation of bone marrow derived mesenchymal stem cells from Bmal1(-/-) mice demonstrate a reduced ability to differentiate into osteoblasts in vitro, which likely explains the observed reductions in osteoblasts and osteocytes, and may contribute to the observed osteopenia. Our data support the role of the circadian clock in the regulation of bone homeostasis and shows that BMAL1 deficiency results in a low bone mass phenotype. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Deficiency of Circadian Clock Protein BMAL1 in Mice Results in a Low Bone Mass Phenotype

    PubMed Central

    Samsa, William E.; Vasanji, Amit; Midura, Ronald J.; Kondratov, Roman V.

    2016-01-01

    The circadian clock is an endogenous time keeping system that controls the physiology and behavior of many organisms. The transcription factor Brain and Muscle ARNT-like Protein 1 (BMAL1) is a component of the circadian clock and necessary for clock function. Bmal1−/− mice display accelerated aging and many accompanying age associated pathologies. Here, we report that mice deficient for BMAL1 have a low bone mass phenotype that is absent at birth and progressively worsens over their lifespan. Accelerated aging of these mice is associated with the formation of bony bridges occurring across the metaphysis to the epiphysis, resulting in shorter long bones. Using micro-computed tomography we show that Bmal1−/− mice have reductions in cortical and trabecular bone volume and other micro-structural parameters and a lower bone mineral density. Histology shows a deficiency of BMAL1 results in a reduced number of active osteoblasts and osteocytes in vivo. Isolation of bone marrow derived mesenchymal stem cells from Bmal1−/− mice demonstrate a reduced ability to differentiate into osteoblasts in vitro, which likely explains the observed reductions in osteoblasts and osteocytes, and may contribute to the observed osteopenia. Our data support the role of the circadian clock in the regulation of bone homeostasis and shows that BMAL1 deficiency results in a low bone mass phenotype. PMID:26789548

  9. Deficiency in DNA damage response of enterocytes accelerates intestinal stem cell aging in Drosophila.

    PubMed

    Park, Joung-Sun; Jeon, Ho-Jun; Pyo, Jung-Hoon; Kim, Young-Shin; Yoo, Mi-Ae

    2018-03-07

    Stem cell dysfunction is closely linked to tissue and organismal aging and age-related diseases, and heavily influenced by the niche cells' environment. The DNA damage response (DDR) is a key pathway for tissue degeneration and organismal aging; however, the precise protective role of DDR in stem cell/niche aging is unclear. The Drosophila midgut is an excellent model to study the biology of stem cell/niche aging because of its easy genetic manipulation and its short lifespan. Here, we showed that deficiency of DDR in Drosophila enterocytes (ECs) accelerates intestinal stem cell (ISC) aging. We generated flies with knockdown of Mre11 , Rad50 , Nbs1 , ATM , ATR , Chk1 , and Chk2 , which decrease the DDR system in ECs. EC-specific DDR depletion induced EC death, accelerated the aging of ISCs, as evidenced by ISC hyperproliferation, DNA damage accumulation, and increased centrosome amplification, and affected the adult fly's survival. Our data indicated a distinct effect of DDR depletion in stem or niche cells on tissue-resident stem cell proliferation. Our findings provide evidence of the essential role of DDR in protecting EC against ISC aging, thus providing a better understanding of the molecular mechanisms of stem cell/niche aging.

  10. Assessment of surface hardness of acrylic resins submitted to accelerated artificial aging.

    PubMed

    Tornavoi, D C; Agnelli, J A M; Lepri, C P; Mazzetto, M O; Botelho, A L; Soares, R G; Dos Reis, A C

    2012-06-01

    The aim of this study was to assess the influence of accelerated artificial aging (AAA) on the surface hardness of acrylic resins. The following three commercial brands of acrylic resins were tested: Vipi Flash (autopolymerized resin), Vipi Wave (microwave heat-polymerized resin) and Vipi Cril (conventional heat-polymerized resin). To perform the tests, 21 test specimens (65x10x3 mm) were made, 7 for each resin. Three surface hardness readings were performed for each test specimen, before and after AAA, and the means were submitted to the following tests: Kolmogorov-Smirnov (P>0.05), Levene Statistic, Two-way ANOVA, Tukey Post Hoc (P<0.05) with the SPSS Statistical Software 17.0. The analysis of the factors showed significant differences in the hardness values (P<0.05). Before aging, the autopolymerized acrylic resin Vipi Flash showed lower hardness values when compared with the heat-polymerized resin Vipi Cril (P=0.001). After aging, the 3 materials showed similar performance when compared among them. The Vipi Cril was the only one affected by AAA and showed lower hardness values after this procedure (Pp=0.003). It may be concluded that accelerated artificial aging influenced surface hardness of heat-polymerized acrylic resin Vipi Cril.

  11. Early-life stress and reproductive cost: A two-hit developmental model of accelerated aging?

    PubMed

    Shalev, Idan; Belsky, Jay

    2016-05-01

    Two seemingly independent bodies of research suggest a two-hit model of accelerated aging, one highlighting early-life stress and the other reproduction. The first, informed by developmental models of early-life stress, highlights reduced longevity effects of early adversity on telomere erosion, whereas the second, informed by evolutionary theories of aging, highlights such effects with regard to reproductive cost (in females). The fact that both early-life adversity and reproductive effort are associated with shorter telomeres and increased oxidative stress raises the prospect, consistent with life-history theory, that these two theoretical frameworks currently informing much research are tapping into the same evolutionary-developmental process of increased senescence and reduced longevity. Here we propose a mechanistic view of a two-hit model of accelerated aging in human females through (a) early-life adversity and (b) early reproduction, via a process of telomere erosion, while highlighting mediating biological embedding mechanisms that might link these two developmental aging processes. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Macrophage Response to UHMWPE Submitted to Accelerated Ageing in Hydrogen Peroxide

    PubMed Central

    Rocha, Magda F.G.; Mansur, Alexandra A.P.; Martins, Camila P.S.; Barbosa-Stancioli, Edel F.; Mansur, Herman S.

    2010-01-01

    Ultra-high molecular weight polyethylene (UHMWPE) has been the most commonly used bearing material in total joint arthroplasty. Wear and oxidation fatigue resistance of UHMWPE are regarded as two important properties to extend the longevity of knee prostheses. The present study investigated the accelerated ageing of UHMWPE in hydrogen peroxide highly oxidative chemical environment. The sliced samples of UHMWPE were oxidized in a hydrogen peroxide solution for 120 days with their total level of oxidation (Iox) characterized by Fourier Transformed Infrared Spectroscopy (FTIR). The potential inflammatory response, cell viability and biocompatibility of such oxidized UHMWPE systems were assessed by a novel biological in vitro assay based on the secretion of nitric oxide (NO) by activated murine macrophages with gamma interferon (IFN-γ) cytokine and lipopolysaccharide (LPS). Furthermore, macrophage morphologies in contact with UHMWPE oxidized surfaces were analyzed by cell spreading-adhesion procedure using scanning electron microscopy (SEM). The results have given significant evidence that the longer the period of accelerated aging of UHMWPE the higher was the macrophage inflammatory equivalent response based on NO secretion analysis. PMID:20721321

  13. Is HIV a model of accelerated or accentuated aging?

    PubMed

    Pathai, Sophia; Bajillan, Hendren; Landay, Alan L; High, Kevin P

    2014-07-01

    Antiretroviral therapy has reduced the incidence of adverse events and early mortality in HIV-infected persons. Despite these benefits, important comorbidities that increase with age (eg, diabetes, cardiovascular disease, cancer, liver disease, and neurocognitive impairment) are more prevalent in HIV-infected persons than in HIV-uninfected persons at every age, and geriatric syndromes such as falls and frailty occur earlier in HIV-infected persons. This raises a critical research question: Does HIV accelerate aging through pathways and mechanisms common to the aging process or is HIV simply an additional risk factor for a wide number of chronic conditions, thus accentuating aging? Extensive literature review. The purpose of this review is to briefly outline the evidence that age-related clinical syndromes are exacerbated by HIV, examine the ways in which HIV is similar, and dissimilar from natural aging, and assess the validity of HIV as a model of premature aging. Specific biomarkers of aging are limited in HIV-infected hosts and impacted by antiretroviral therapy, and a high rate of modifiable life style confounders (eg, smoking, substance abuse, alcohol) and coinfections (eg, hepatitis) in HIV-infected participants. There is a need for validated biomarkers of aging in the context of HIV. Despite these differences, welldesigned studies of HIV-infected participants are likely to provide new opportunities to better understand the mechanisms that lead to aging and age-related diseases. © The Author 2013. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  14. Dysregulated physiological stress systems and accelerated cellular aging.

    PubMed

    Révész, Dóra; Verhoeven, Josine E; Milaneschi, Yuri; de Geus, Eco J C N; Wolkowitz, Owen M; Penninx, Brenda W J H

    2014-06-01

    Exposure to chronic stressors is associated with accelerated biological aging as indicated by reduced leukocyte telomere length (LTL). This impact could be because of chronic overactivation of the body's physiological stress systems. This study examined the associations between LTL and the immune system, hypothalamic-pituitary-adrenal axis and autonomic nervous system. LTL was assessed in 2936 adults from the Netherlands Study of Depression and Anxiety. Inflammation markers (interleukin-6, c-reactive protein, tumor necrosis factor-alpha), hypothalamic-pituitary-adrenal-axis indicators (salivary cortisol awakening curve [area under the curve indicators, with respect to the ground and increase], evening levels, 0.5 mg dexamethasone cortisol suppression ratio), and autonomic nervous system measures (heart rate, respiratory sinus arrhythmia, pre-ejection period) were determined. Linear regression analyses were performed and adjusted for sociodemographic, lifestyle and clinical factors. Shorter LTL was significantly associated with higher c-reactive protein, interleukin-6, area under the curve with respect to increase, and heart rate. A cumulative index score was calculated based on the number of highest tertiles of these 4 stress markers. LTL demonstrated a significant gradient within subjects ranging from having zero (5528 base pairs) to having 4 elevated stress markers (5371 base pairs, p for trend = 0.002), corresponding to a difference of 10 years of accelerated biological aging. Contrary to the expectations, shorter LTL was also associated with longer pre-ejection period, indicating lower sympathetic tone. This large-scale study showed that inflammation, high awakening cortisol response, and increased heart rate are associated with shorter LTL, especially when they are dysregulated cumulatively. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Accelerated Post-Weld Natural Ageing in Ultrasonic Welding Aluminium 6111-T4 Automotive Sheet

    NASA Astrophysics Data System (ADS)

    Chen, Ying-Chun; Prangnell, Phil

    In contrast to previously published reports, it is shown that there is an observable HAZ when ultrasonic spot welding (USW) automotive alloys, like AA6111-T4, the severity of which depends on the welding energy. Immediately after welding, softening is seen relative to the T4 condition, but this is rapidly recovered by natural ageing, which masks the presence of a HAZ, and the weld strength eventually exceeds that of the parent material. This behaviour is caused by dissolution of the solute clusters/GPZs in the T4 sheet, due to the high weld temperatures (> 400 °C), combined with accelerated post-weld natural ageing to a more advanced state than in the parent material. Modelling has demonstrated that this accelerated natural ageing behaviour can be attributed to an excess vacancy concentration generated by the USW process.

  16. Ontogenetic loss of phenotypic plasticity of age at metamorphosis in tadpoles

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hensley, F.R.

    1993-12-01

    Amphibian larvae exhibit phenotypic plasticity in size at metamorphosis and duration of the larval period. I used Pseudacris crucifer tadpoles to test two models for predicting tadpole age and size at metamorphosis under changing environmental conditions. The Wilbur-Collins model states that metamorphosis is initiated as a function of a tadpole's size and relative growth rate, and predicts that changes in growth rate throughout the larval period affect age and size at metamorphosis. An alternative model, the fixed-rate model, states that age at metamorphosis is fixed early in larval life, and subsequent changes in growth rate will have no effect onmore » the length of the larval period. My results confirm that food supplies affect both age and size at metamorphosis, but developmental rates became fixed at approximately Gosner (1960) stages 35-37. Neither model completely predicted these results. I suggest that the generally accepted Wilbur-Collins model is improved by incorporating a point of fixed developmental timing. Growth trajectories predicted from this modified model fit the results of this study better than trajectories based on either of the original models. The results of this study suggests a constraint that limits the simultaneous optimization of age and size at metamorphosis. 32 refs., 5 figs., 1 tab.« less

  17. Monitoring migration and transformation of nanomaterials in polymeric composites during accelerated aging

    NASA Astrophysics Data System (ADS)

    Vilar, G.; Fernández-Rosas, E.; Puntes, V.; Jamier, V.; Aubouy, L.; Vázquez-Campos, S.

    2013-04-01

    The incorporation of small amounts of nanoadditives in polymeric compounds can introduce new mechanical, physical, electrical, magnetic, thermal and/or optical properties. The properties of these advanced materials have enabled new applications in several industrial sectors (electronics, automotive, textile...). In particular, for the nanomaterials (NM) described in this work, multi-walled carbon nanotubes (MWCNT) and silicon dioxide nanoparticles (SiO2 NP), the following properties have been described: MWCNT act as nucleating agents in thermoplastics, and change viscosity, affecting dispersion, orientation, and therefore mechanical, thermal, and electrical properties; and SiO2 NP act as flame retardant and display improved electrical and mechanical properties. The work described here is focused on the evaluation of the migration and transformation of NM included in polymer nanocomposites (NC) during accelerated climatic ageing. To this aim, we generated polyamide 6 (PA6) NC with different degree of compatibility between the NM and the polymeric matrix. These NC were submitted to accelerated aging conditions to simulate outdoor conditions (simulation of the use phase of the polymeric NC). The NC contain as nanofillers MWCNT and SiO2 NP with different surface properties to influence the compatibility with the polymeric matrix. The generated NC were evaluated by scanning electron microscopy (SEM), transmission electron microscopy (TEM) with Energy-dispersive X-ray spectroscopy (EDX), thermogravimetry (TGA) and differential scanning calorimetry (DSC) before and after the aging process, to monitor the compatibility of the NM with the matrix: dispersion within the matrix, migration during aging, and modification of the polymer properties. The dispersion of SiO2 NP in the NC depended on their compatibility with the matrix. However, independently of their compatibility with the matrix, SiO2 NP were aggregated at the end of the accelerated aging process. In addition

  18. Genetic Polymorphisms and the Phenotypic Characterization of Individuals with Early Age-Related Macular Degeneration.

    PubMed

    Oeverhaus, Michael; Meyer Zu Westrup, Verena; Dietzel, Martha; Hense, Hans-Werner; Pauleikhoff, Daniel

    2017-01-01

    While the importance of risk polymorphisms for the pathogenesis of age-related macular degeneration (AMD) is well established, their impact on morphological and functional phenotypes is largely unclear. We aimed to characterize individual phenotypes in patients who were either homozygous for a risk allele in the CFH gene, ARMS2 gene, or both as compared to non-carriers. Patients with early AMD (n = 85) were assessed during a follow-up examination of a prospective study (MARS) with multimodal diagnostics including SD-OCT and microperimetry. Compared to non-carriers, OCT scans revealed lower retinal thickness in patients homozygous for CFH or ARMS2, which was caused by a significantly reduced photoreceptor layer. The number and ultrastructure of drusen were also significantly different. These findings indicate that patients with risk alleles demonstrate distinct phenotypic differences of morphology and function as compared to non-carriers. In particular in the CFH group, a loss of photoreceptors occurred concomitantly with reduced retinal sensitivity. Further studies might help to better understand the pathophysiology. © 2017 S. Karger AG, Basel.

  19. Do US Black Women Experience Stress-Related Accelerated Biological Aging?

    PubMed Central

    Hicken, Margaret T.; Pearson, Jay A.; Seashols, Sarah J.; Brown, Kelly L.; Cruz, Tracey Dawson

    2010-01-01

    We hypothesize that black women experience accelerated biological aging in response to repeated or prolonged adaptation to subjective and objective stressors. Drawing on stress physiology and ethnographic, social science, and public health literature, we lay out the rationale for this hypothesis. We also perform a first population-based test of its plausibility, focusing on telomere length, a biomeasure of aging that may be shortened by stressors. Analyzing data from the Study of Women's Health Across the Nation (SWAN), we estimate that at ages 49–55, black women are 7.5 years biologically “older” than white women. Indicators of perceived stress and poverty account for 27% of this difference. Data limitations preclude assessing objective stressors and also result in imprecise estimates, limiting our ability to draw firm inferences. Further investigation of black-white differences in telomere length using large-population-based samples of broad age range and with detailed measures of environmental stressors is merited. PMID:20436780

  20. Acceleration of Age-Associated Methylation Patterns in HIV-1-Infected Adults

    PubMed Central

    Sehl, Mary; Sinsheimer, Janet S.; Hultin, Patricia M.; Hultin, Lance E.; Quach, Austin; Martínez-Maza, Otoniel; Horvath, Steve; Vilain, Eric; Jamieson, Beth D.

    2015-01-01

    Patients with treated HIV-1-infection experience earlier occurrence of aging-associated diseases, raising speculation that HIV-1-infection, or antiretroviral treatment, may accelerate aging. We recently described an age-related co-methylation module comprised of hundreds of CpGs; however, it is unknown whether aging and HIV-1-infection exert negative health effects through similar, or disparate, mechanisms. We investigated whether HIV-1-infection would induce age-associated methylation changes. We evaluated DNA methylation levels at >450,000 CpG sites in peripheral blood mononuclear cells (PBMC) of young (20-35) and older (36-56) adults in two separate groups of participants. Each age group for each data set consisted of 12 HIV-1-infected and 12 age-matched HIV-1-uninfected samples for a total of 96 samples. The effects of age and HIV-1 infection on methylation at each CpG revealed a strong correlation of 0.49, p<1 x10-200 and 0.47, p<1x10-200. Weighted gene correlation network analysis (WGCNA) identified 17 co-methylation modules; module 3 (ME3) was significantly correlated with age (cor=0.70) and HIV-1 status (cor=0.31). Older HIV-1+ individuals had a greater number of hypermethylated CpGs across ME3 (p=0.015). In a multivariate model, ME3 was significantly associated with age and HIV status (Data set 1: βage= 0.007088, p=2.08 x 10-9; βHIV= 0.099574, p=0.0011; Data set 2: βage= 0.008762, p=1.27x 10-5; βHIV= 0.128649, p= 0.0001). Using this model, we estimate that HIV-1 infection accelerates age-related methylation by approximately 13.7 years in data set 1 and 14.7 years in data set 2. The genes related to CpGs in ME3 are enriched for polycomb group target genes known to be involved in cell renewal and aging. The overlap between ME3 and an aging methylation module found in solid tissues is also highly significant (Fisher-exact p=5.6 x 10-6, odds ratio=1.91). These data demonstrate that HIV-1 infection is associated with methylation patterns that are similar to

  1. Towards measurement of the Healthy Ageing Phenotype in lifestyle-based intervention studies.

    PubMed

    Lara, Jose; Godfrey, Alan; Evans, Elizabeth; Heaven, Ben; Brown, Laura J E; Barron, Evelyn; Rochester, Lynn; Meyer, Thomas D; Mathers, John C

    2013-10-01

    Given the biological complexity of the ageing process, there is no single, simple and reliable measure of how healthily someone is ageing. Intervention studies need a panel of measures which capture key features of healthy ageing. To help guide our research in this area, we have adopted the concept of the "Healthy Ageing Phenotype" (HAP) and this study aimed to (i) identify the most important features of the HAP and (ii) identify/develop tools for measurement of those features. After a comprehensive assessment of the literature we selected the following domains: physiological and metabolic health, physical capability, cognitive function, social wellbeing, and psychological wellbeing which we hoped would provide a reasonably holistic characterisation of the HAP. We reviewed the literature and identified systematic reviews and/or meta-analysis of cohort studies, and clinical guidelines on outcome measures of these domains relevant to the HAP. Selection criteria for these measures included: frequent use in longitudinal studies of ageing; expected to change with age; evidence for strong association with/prediction of ageing-related phenotypes such as morbidity, mortality and lifespan; whenever possible, focus on studies measuring these outcomes in populations rather than on individuals selected on the basis of a particular disease; (bio)markers that respond to (lifestyle-based) intervention. Proposed markers were exposed to critique in a Workshop held in Newcastle, UK in October 2012. We have selected a tentative panel of (bio)markers of physiological and metabolic health, physical capability, cognitive function, social wellbeing, and psychological wellbeing which we propose may be useful in characterising the HAP and which may have utility as outcome measures in intervention studies. In addition, we have identified a number of tools which could be applied in community-based intervention studies designed to enhance healthy ageing. We have proposed, tentatively, a panel

  2. 175.4 The Relationship of Aging and Inflammatory Biomarkers to Gray Matter Volume and Episodic Memory Performance in Schizophrenia: Evidence of Pathological Accelerated Aging

    PubMed Central

    Gama, Clarissa

    2017-01-01

    Abstract Background: Schizophrenia (SZ) is associated with increased somatic morbidity and mortality, in addition to cognitive impairments similar to those seen in normal aging, which may suggest that pathological accelerated aging occurs in SZ. Therefore, we aim to evaluate the relationships of age, telomere length (TL) and CCL11 (aging and inflammatory biomarkers), and gray matter volumes (GM) to episodic memory performance in individuals with SZ compared to healthy controls (HC). Methods: 112 participants (48 SZ and 64 HC) underwent clinical and memory assessments, structural MRI, and had their peripheral blood drawn for biomarkers analysis. Comparisons of group means and correlations were performed. Results: Participants with SZ had decreased TL and GM residual volume, increased CCL11, and worse memory performance compared to HC. In SZ, shorter TL was related to increased CCL11, and they were both related to reduced GM residual volume, all of which were related to worse memory performance. Older age was only associated with reduced GM, but longer duration of illness was related with all the aforementioned variables. Younger age of disease onset was related with increased CCL11 levels and worse memory performance. In HC, there were no significant correlations except for between memory and GM. Conclusion: Our results are consistent with accelerated aging in SZ. These results may indicate that it is not age itself, but the impact of the disease associated with a pathological accelerated aging that leads to impaired outcomes in SZ. Akira Sawa, johns Hopkins University, Johns Hopkins Hospital and Medical Institutions

  3. Microglia change from a reactive to an age-like phenotype with the time in culture.

    PubMed

    Caldeira, Cláudia; Oliveira, Ana F; Cunha, Carolina; Vaz, Ana R; Falcão, Ana S; Fernandes, Adelaide; Brites, Dora

    2014-01-01

    Age-related neurodegenerative diseases have been associated with chronic neuroinflammation and microglia activation. However, cumulative evidence supports that inflammation only occurs at an early stage once microglia change the endogenous characteristics with aging and switch to irresponsive/senescent and dystrophic phenotypes with disease progression. Thus, it will be important to have the means to assess the role of reactive and aged microglia when studying advanced brain neurodegeneration processes and age-associated related disorders. Yet, most studies are done with microglia from neonates since there are no adequate means to isolate degenerating microglia for experimentation. Indeed, only a few studies report microglia isolation from aged animals, using either short-term cultures or high concentrations of mitogens in the medium, which trigger microglia reactivity. The purpose of this study was to develop an experimental process to naturally age microglia after isolation from neonatal mice and to characterize the cultured cells at 2 days in vitro (DIV), 10 DIV, and 16 DIV. We found that 2 DIV (young) microglia had predominant amoeboid morphology and markers of stressed/reactive phenotype. In contrast, 16 DIV (aged) microglia evidenced ramified morphology and increased matrix metalloproteinase (MMP)-2 activation, as well as reduced MMP-9, glutamate release and nuclear factor kappa-B activation, in parallel with decreased expression of Toll-like receptor (TLR)-2 and TLR-4, capacity to migrate and phagocytose. These findings together with the reduced expression of microRNA (miR)-124, and miR-155, decreased autophagy, enhanced senescence associated beta-galactosidase activity and elevated miR-146a expression, are suggestive that 16 DIV cells mainly correspond to irresponsive/senescent microglia. Data indicate that the model represent an opportunity to understand and control microglial aging, as well as to explore strategies to recover microglia surveillance

  4. Microglia change from a reactive to an age-like phenotype with the time in culture

    PubMed Central

    Caldeira, Cláudia; Oliveira, Ana F.; Cunha, Carolina; Vaz, Ana R.; Falcão, Ana S.; Fernandes, Adelaide; Brites, Dora

    2014-01-01

    Age-related neurodegenerative diseases have been associated with chronic neuroinflammation and microglia activation. However, cumulative evidence supports that inflammation only occurs at an early stage once microglia change the endogenous characteristics with aging and switch to irresponsive/senescent and dystrophic phenotypes with disease progression. Thus, it will be important to have the means to assess the role of reactive and aged microglia when studying advanced brain neurodegeneration processes and age-associated related disorders. Yet, most studies are done with microglia from neonates since there are no adequate means to isolate degenerating microglia for experimentation. Indeed, only a few studies report microglia isolation from aged animals, using either short-term cultures or high concentrations of mitogens in the medium, which trigger microglia reactivity. The purpose of this study was to develop an experimental process to naturally age microglia after isolation from neonatal mice and to characterize the cultured cells at 2 days in vitro (DIV), 10 DIV, and 16 DIV. We found that 2 DIV (young) microglia had predominant amoeboid morphology and markers of stressed/reactive phenotype. In contrast, 16 DIV (aged) microglia evidenced ramified morphology and increased matrix metalloproteinase (MMP)-2 activation, as well as reduced MMP-9, glutamate release and nuclear factor kappa-B activation, in parallel with decreased expression of Toll-like receptor (TLR)-2 and TLR-4, capacity to migrate and phagocytose. These findings together with the reduced expression of microRNA (miR)-124, and miR-155, decreased autophagy, enhanced senescence associated beta-galactosidase activity and elevated miR-146a expression, are suggestive that 16 DIV cells mainly correspond to irresponsive/senescent microglia. Data indicate that the model represent an opportunity to understand and control microglial aging, as well as to explore strategies to recover microglia surveillance

  5. Long-term exposure to air pollution is associated with biological aging

    PubMed Central

    Ward-Caviness, Cavin K.; Nwanaji-Enwerem, Jamaji C.; Wolf, Kathrin; Wahl, Simone; Colicino, Elena; Trevisi, Letizia; Kloog, Itai; Just, Allan C.; Vokonas, Pantel; Cyrys, Josef; Gieger, Christian; Schwartz, Joel; Baccarelli, Andrea A.; Schneider, Alexandra; Peters, Annette

    2016-01-01

    Long-term exposure to air pollution is associated with age-related diseases. We explored the association between accelerated biological aging and air pollution, a potential mechanism linking air pollution and health. We estimated long-term exposure to PM10, PM2.5, PM2.5 absorbance/black carbon (BC), and NOx via land-use regression models in individuals from the KORA F4 cohort. Accelerated biological aging was assessed using telomere length (TeloAA) and three epigenetic measures: DNA methylation age acceleration (DNAmAA), extrinsic epigenetic age acceleration (correlated with immune cell counts, EEAA), and intrinsic epigenetic age acceleration (independent of immune cell counts, IEAA). We also investigated sex-specific associations between air pollution and biological aging, given the published association between sex and aging measures. In KORA an interquartile range (0.97 μg/m3) increase in PM2.5 was associated with a 0.33 y increase in EEAA (CI = 0.01, 0.64; P = 0.04). BC and NOx (indicators or traffic exposure) were associated with DNAmAA and IEAA in women, while TeloAA was inversely associated with BC in men. We replicated this inverse BC-TeloAA association in the Normative Aging Study, a male cohort based in the USA. A multiple phenotype analysis in KORA F4 combining all aging measures showed that BC and PM10 were broadly associated with biological aging in men. Thus, we conclude that long-term exposure to air pollution is associated with biological aging measures, potentially in a sex-specific manner. However, many of the associations were relatively weak and further replication of overall and sex-specific associations is warranted. PMID:27793020

  6. Long-term exposure to air pollution is associated with biological aging.

    PubMed

    Ward-Caviness, Cavin K; Nwanaji-Enwerem, Jamaji C; Wolf, Kathrin; Wahl, Simone; Colicino, Elena; Trevisi, Letizia; Kloog, Itai; Just, Allan C; Vokonas, Pantel; Cyrys, Josef; Gieger, Christian; Schwartz, Joel; Baccarelli, Andrea A; Schneider, Alexandra; Peters, Annette

    2016-11-15

    Long-term exposure to air pollution is associated with age-related diseases. We explored the association between accelerated biological aging and air pollution, a potential mechanism linking air pollution and health. We estimated long-term exposure to PM10, PM2.5, PM2.5 absorbance/black carbon (BC), and NOx via land-use regression models in individuals from the KORA F4 cohort. Accelerated biological aging was assessed using telomere length (TeloAA) and three epigenetic measures: DNA methylation age acceleration (DNAmAA), extrinsic epigenetic age acceleration (correlated with immune cell counts, EEAA), and intrinsic epigenetic age acceleration (independent of immune cell counts, IEAA). We also investigated sex-specific associations between air pollution and biological aging, given the published association between sex and aging measures. In KORA an interquartile range (0.97 µg/m3) increase in PM2.5 was associated with a 0.33 y increase in EEAA (CI = 0.01, 0.64; P = 0.04). BC and NOx (indicators or traffic exposure) were associated with DNAmAA and IEAA in women, while TeloAA was inversely associated with BC in men. We replicated this inverse BC-TeloAA association in the Normative Aging Study, a male cohort based in the USA. A multiple phenotype analysis in KORA F4 combining all aging measures showed that BC and PM10 were broadly associated with biological aging in men. Thus, we conclude that long-term exposure to air pollution is associated with biological aging measures, potentially in a sex-specific manner. However, many of the associations were relatively weak and further replication of overall and sex-specific associations is warranted.

  7. Experimental induction of type 2 diabetes in aging-accelerated mice triggered Alzheimer-like pathology and memory deficits.

    PubMed

    Mehla, Jogender; Chauhan, Balwantsinh C; Chauhan, Neelima B

    2014-01-01

    Alzheimer's disease (AD) is an age-dependent neurodegenerative disease constituting ~95% of late-onset non-familial/sporadic AD, and only ~5% accounting for early-onset familial AD. Availability of a pertinent model representing sporadic AD is essential for testing candidate therapies. Emerging evidence indicates a causal link between diabetes and AD. People with diabetes are >1.5-fold more likely to develop AD. Senescence-accelerated mouse model (SAMP8) of accelerated aging displays many features occurring early in AD. Given the role played by diabetes in the pre-disposition of AD, and the utility of SAMP8 non-transgenic mouse model of accelerated aging, we examined if high fat diet-induced experimental type 2 diabetes in SAMP8 mice will trigger pathological aging of the brain. Results showed that compared to non-diabetic SAMP8 mice, diabetic SAMP8 mice exhibited increased cerebral amyloid-β, dysregulated tau-phosphorylating glycogen synthase kinase 3β, reduced synaptophysin immunoreactivity, and displayed memory deficits, indicating Alzheimer-like changes. High fat diet-induced type 2 diabetic SAMP8 mice may represent the metabolic model of AD.

  8. Accelerated Aging System for Prognostics of Power Semiconductor Devices

    NASA Technical Reports Server (NTRS)

    Celaya, Jose R.; Vashchenko, Vladislav; Wysocki, Philip; Saha, Sankalita

    2010-01-01

    Prognostics is an engineering discipline that focuses on estimation of the health state of a component and the prediction of its remaining useful life (RUL) before failure. Health state estimation is based on actual conditions and it is fundamental for the prediction of RUL under anticipated future usage. Failure of electronic devices is of great concern as future aircraft will see an increase of electronics to drive and control safety-critical equipment throughout the aircraft. Therefore, development of prognostics solutions for electronics is of key importance. This paper presents an accelerated aging system for gate-controlled power transistors. This system allows for the understanding of the effects of failure mechanisms, and the identification of leading indicators of failure which are essential in the development of physics-based degradation models and RUL prediction. In particular, this system isolates electrical overstress from thermal overstress. Also, this system allows for a precise control of internal temperatures, enabling the exploration of intrinsic failure mechanisms not related to the device packaging. By controlling the temperature within safe operation levels of the device, accelerated aging is induced by electrical overstress only, avoiding the generation of thermal cycles. The temperature is controlled by active thermal-electric units. Several electrical and thermal signals are measured in-situ and recorded for further analysis in the identification of leading indicators of failures. This system, therefore, provides a unique capability in the exploration of different failure mechanisms and the identification of precursors of failure that can be used to provide a health management solution for electronic devices.

  9. Accelerated age-related cognitive decline and neurodegeneration, caused by deficient DNA repair.

    PubMed

    Borgesius, Nils Z; de Waard, Monique C; van der Pluijm, Ingrid; Omrani, Azar; Zondag, Gerben C M; van der Horst, Gijsbertus T J; Melton, David W; Hoeijmakers, Jan H J; Jaarsma, Dick; Elgersma, Ype

    2011-08-31

    Age-related cognitive decline and neurodegenerative diseases are a growing challenge for our societies with their aging populations. Accumulation of DNA damage has been proposed to contribute to these impairments, but direct proof that DNA damage results in impaired neuronal plasticity and memory is lacking. Here we take advantage of Ercc1(Δ/-) mutant mice, which are impaired in DNA nucleotide excision repair, interstrand crosslink repair, and double-strand break repair. We show that these mice exhibit an age-dependent decrease in neuronal plasticity and progressive neuronal pathology, suggestive of neurodegenerative processes. A similar phenotype is observed in mice where the mutation is restricted to excitatory forebrain neurons. Moreover, these neuron-specific mutants develop a learning impairment. Together, these results suggest a causal relationship between unrepaired, accumulating DNA damage, and age-dependent cognitive decline and neurodegeneration. Hence, accumulated DNA damage could therefore be an important factor in the onset and progression of age-related cognitive decline and neurodegenerative diseases.

  10. Accelerated cognitive aging following severe traumatic brain injury: A review.

    PubMed

    Wood, Rodger Ll

    2017-01-01

    The primary objective of this review was to examine relevant clinical and experimental literatures for information on the long-term cognitive impact of serious traumatic brain injury (TBI) with regard to the process of cognitive aging. Online journal databases were queried for studies pertaining to cognitive aging in neurologically healthy populations, as well as the late cognitive effects of serious TBI. Additional studies were identified through searching bibliographies of related publications and using Google search engine. Problems of cognition exhibited by young adults after TBI resemble many cognitive weaknesses of attention deficit and poor working memory that are usually seen in an elderly population who have no neurological history. The current state of the literature provides support for the argument that TBI can result in diminished cognitive reserve which may accelerate the normal process of cognitive decline, leading to premature aging, potentially increasing the risk of dementia.

  11. Acrylamide induces accelerated endothelial aging in a human cell model.

    PubMed

    Sellier, Cyril; Boulanger, Eric; Maladry, François; Tessier, Frédéric J; Lorenzi, Rodrigo; Nevière, Rémi; Desreumaux, Pierre; Beuscart, Jean-Baptiste; Puisieux, François; Grossin, Nicolas

    2015-09-01

    Acrylamide (AAM) has been recently discovered in food as a Maillard reaction product. AAM and glycidamide (GA), its metabolite, have been described as probably carcinogenic to humans. It is widely established that senescence and carcinogenicity are closely related. In vitro, endothelial aging is characterized by replicative senescence in which primary cells in culture lose their ability to divide. Our objective was to assess the effects of AAM and GA on human endothelial cell senescence. Human umbilical vein endothelial cells (HUVECs) cultured in vitro were used as model. HUVECs were cultured over 3 months with AAM or GA (1, 10 or 100 μM) until growth arrest. To analyze senescence, β-galactosidase activity and telomere length of HUVECs were measured by cytometry and semi-quantitative PCR, respectively. At all tested concentrations, AAM or GA reduced cell population doubling compared to the control condition (p < 0.001). β-galactosidase activity in endothelial cells was increased when exposed to AAM (≥10 μM) or GA (≥1 μM) (p < 0.05). AAM (≥10 μM) or GA (100 μM) accelerated telomere shortening in HUVECs (p < 0.05). In conclusion, in vitro chronic exposure to AAM or GA at low concentrations induces accelerated senescence. This result suggests that an exposure to AAM might contribute to endothelial aging. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Anti-aging treatments slow propagation of synucleinopathy by restoring lysosomal function.

    PubMed

    Kim, Dong-Kyu; Lim, Hee-Sun; Kawasaki, Ichiro; Shim, Yhong-Hee; Vaikath, Nishant N; El-Agnaf, Omar M A; Lee, He-Jin; Lee, Seung-Jae

    2016-10-02

    Aging is the major risk factor for neurodegenerative diseases that are also associated with impaired proteostasis, resulting in abnormal accumulation of protein aggregates. However, the role of aging in development and progression of disease remains elusive. Here, we used Caenorhabditis elegans models to show that aging-promoting genetic variations accelerated the rate of cell-to-cell transmission of SNCA/α-synuclein aggregates, hallmarks of Parkinson disease, and the progression of disease phenotypes, such as nerve degeneration, behavioral deficits, and reduced life span. Genetic and pharmacological anti-aging manipulations slowed the spread of aggregates and the associated phenotypes. Lysosomal degradation was significantly impaired in aging models, while anti-aging treatments reduced the impairment. Transgenic expression of hlh-30p::hlh-30, the master controller of lysosomal biogenesis, alleviated intercellular transmission of aggregates in the aging model. Our results demonstrate that the rate of aging closely correlates with the rate of aggregate propagation and that general anti-aging treatments can slow aggregate propagation and associated disease progression by restoring lysosomal function.

  13. Transcriptome Analysis of Human Injured Meniscus Reveals a Distinct Phenotype of Meniscus Degeneration with Aging

    PubMed Central

    Rai, Muhammad Farooq; Patra, Debabrata; Sandell, Linda J.; Brophy, Robert H.

    2013-01-01

    Objective Meniscus tears are associated with a heightened risk for osteoarthritis. We aimed to advance our understanding of the metabolic state of human injured meniscus at the time of arthroscopic partial meniscectomy through transcriptome-wide analysis of gene expression in relation to patient age and degree of cartilage chondrosis. Methods The degree of chondrosis of knee cartilage was recorded at the time of meniscectomy in symptomatic patients without radiographic osteoarthritis. RNA preparations from resected menisci (N=12) were subjected to transcriptome-wide microarray and QuantiGene Plex analyses. The relative changes in gene expression variation with age and chondrosis were analyzed and integrated biological processes were investigated computationally. Results We identified a set of genes in torn meniscus that were differentially expressed with age and chondrosis. There were 866 genes differentially regulated (≥1.5-fold; P<0.05) with age and 49 with chondrosis. In older patients, genes associated with cartilage and skeletal development and extracellular matrix synthesis were repressed while those involved in immune response, inflammation, cell cycle, and cellular proliferation were stimulated. With chondrosis, genes representing cell catabolism (cAMP catabolic process) and tissue and endothelial cell development were repressed and those involved in T cell differentiation and apoptosis were elevated. Conclusion Differences in age-related gene expression suggest that in older adults, meniscal cells might de-differentiate and initiate a proliferative phenotype. Conversely, meniscal cells in younger patients appear to respond to injury, but maintain the differentiated phenotype. Definitive molecular signatures identified in damaged meniscus could be segregated largely with age and, to a lesser extent, with chondrosis. PMID:23658108

  14. Motor impairment: a new ethanol withdrawal phenotype in mice

    PubMed Central

    Philibin, Scott D.; Cameron, Andy J.; Metten, Pamela; Crabbe, John C.

    2015-01-01

    Alcoholism is a complex disorder with genetic and environmental risk factors. The presence of withdrawal symptoms is one criterion for alcohol dependence. Genetic animal models have followed a reductionist approach by quantifying various effects of ethanol withdrawal separately. Different ethanol withdrawal symptoms may have distinct genetic etiologies, and therefore differentiating distinct neurobiological mechanisms related to separate signs of withdrawal would increase our understanding of various aspects of the complex phenotype. This study establishes motor incoordination as a new phenotype of alcohol withdrawal in mice. Mice were made physically dependent on ethanol by exposure to ethanol vapor for 72 h. The effects of ethanol withdrawal in mice from different genetic backgrounds were measured on the accelerating rotarod, a simple motor task. Ethanol withdrawal disrupted accelerating rotarod behavior in mice. The disruptive effects of withdrawal suggest a performance rather than a learning deficit. Inbred strain comparisons suggest genetic differences in magnitude of this withdrawal phenotype. The withdrawal-induced deficits were not correlated with the selection response difference in handling convulsion severity in selectively bred Withdrawal Seizure-Prone and Withdrawal Seizure-Resistant lines. The accelerating rotarod seems to be a simple behavioral measure of ethanol withdrawal that is suitable for comparing genotypes. PMID:18690115

  15. Surface degradation of polymer insulators under accelerated climatic aging in weather-ometer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Xu, G.; McGrath, P.B.; Burns, C.W.

    1996-12-31

    Climatic aging experiments were conducted on two types of outdoor polymer insulators by using a programmable weather-ometer. The housing materials for the insulators were silicone rubber (SR) and ethylene propylene diene monomer (EPDM). The accelerated aging stresses were comprised of ultraviolet radiation, elevated temperature, temperature cycling, thermal shock and high humidity. Their effects on the insulator surface conditions and electrical performance wee examined through visual inspection and SEM studies, contact angle measurements, thermogravimetric analysis (TGA), energy dispersive spectroscopy (EDS) analysis, and 50% impulse flashover voltage tests. The results showed a significant damage on the insulator surface caused by some ofmore » the imposed aging stresses. The EDS analysis suggested a photooxidation process that happened on the insulator surface during the aging period.« less

  16. Nuclear lamina defects cause ATM-dependent NF-κB activation and link accelerated aging to a systemic inflammatory response.

    PubMed

    Osorio, Fernando G; Bárcena, Clea; Soria-Valles, Clara; Ramsay, Andrew J; de Carlos, Félix; Cobo, Juan; Fueyo, Antonio; Freije, José M P; López-Otín, Carlos

    2012-10-15

    Alterations in the architecture and dynamics of the nuclear lamina have a causal role in normal and accelerated aging through both cell-autonomous and systemic mechanisms. However, the precise nature of the molecular cues involved in this process remains incompletely defined. Here we report that the accumulation of prelamin A isoforms at the nuclear lamina triggers an ATM- and NEMO-dependent signaling pathway that leads to NF-κB activation and secretion of high levels of proinflammatory cytokines in two different mouse models of accelerated aging (Zmpste24(-/-) and Lmna(G609G/G609G) mice). Causal involvement of NF-κB in accelerated aging was demonstrated by the fact that both genetic and pharmacological inhibition of NF-κB signaling prevents age-associated features in these animal models, significantly extending their longevity. Our findings provide in vivo proof of principle for the feasibility of pharmacological modulation of the NF-κB pathway to slow down the progression of physiological and pathological aging.

  17. Service Lifetime Estimation of EPDM Rubber Based on Accelerated Aging Tests

    NASA Astrophysics Data System (ADS)

    Liu, Jie; Li, Xiangbo; Xu, Likun; He, Tao

    2017-04-01

    Service lifetime of ethylene propylene diene monomer (EPDM) rubber at room temperature (25 °C) was estimated based on accelerated aging tests. The study followed sealing stress loss on compressed cylinder samples by compression stress relaxation methods. The results showed that the cylinder samples of EPDM can quickly reach the physical relaxation equilibrium by using the over-compression method. The non-Arrhenius behavior occurred at the lowest aging temperature. A significant linear relationship was observed between compression set values and normalized stress decay results, and the relationship was not related to the ambient temperature of aging. It was estimated that the sealing stress loss in view of practical application would occur after around 86.8 years at 25 °C. The estimations at 25 °C based on the non-Arrhenius behavior were in agreement with compression set data from storage aging tests in natural environment.

  18. Rapamycin suppresses brain aging in senescence-accelerated OXYS rats.

    PubMed

    Kolosova, Nataliya G; Vitovtov, Anton O; Muraleva, Natalia A; Akulov, Andrey E; Stefanova, Natalia A; Blagosklonny, Mikhail V

    2013-06-01

    Cellular and organismal aging are driven in part by the MTOR (mechanistic target of rapamycin) pathway and rapamycin extends life span inC elegans, Drosophila and mice. Herein, we investigated effects of rapamycin on brain aging in OXYS rats. Previously we found, in OXYS rats, an early development of age-associated pathological phenotypes similar to several geriatric disorders in humans, including cerebral dysfunctions. Behavioral alterations as well as learning and memory deficits develop by 3 months. Here we show that rapamycin treatment (0.1 or 0.5 mg/kg as a food mixture daily from the age of 1.5 to 3.5 months) decreased anxiety and improved locomotor and exploratory behavior in OXYS rats. In untreated OXYS rats, MRI revealed an increase of the area of hippocampus, substantial hydrocephalus and 2-fold increased area of the lateral ventricles. Rapamycin treatment prevented these abnormalities, erasing the difference between OXYS and Wister rats (used as control). All untreated OXYS rats showed signs of neurodegeneration, manifested by loci of demyelination. Rapamycin decreased the percentage of animals with demyelination and the number of loci. Levels of Tau and phospho-Tau (T181) were increased in OXYS rats (compared with Wistar). Rapamycin significantly decreased Tau and inhibited its phosphorylation in the hippocampus of OXYS and Wistar rats. Importantly, rapamycin treatment caused a compensatory increase in levels of S6 and correspondingly levels of phospo-S6 in the frontal cortex, indicating that some downstream events were compensatory preserved, explaining the lack of toxicity. We conclude that rapamycin in low chronic doses can suppress brain aging.

  19. Rapamycin suppresses brain aging in senescence-accelerated OXYS rats

    PubMed Central

    Kolosova, Nataliya G.; Vitovtov, Anton O.; Muraleva, Natalia A; Akulov, Andrey E.; Stefanova, Natalia A.; Blagosklonny, Mikhail V.

    2013-01-01

    Cellular and organismal aging are driven in part by the MTOR (mechanistic target of rapamycin) pathway and rapamycin extends life span in C elegans, Drosophila and mice. Herein, we investigated effects of rapamycin on brain aging in OXYS rats. Previously we found, in OXYS rats, an early development of age-associated pathological phenotypes similar to several geriatric disorders in humans, including cerebral dysfunctions. Behavioral alterations as well as learning and memory deficits develop by 3 months. Here we show that rapamycin treatment (0.1 or 0.5 mg/kg as a food mixture daily from the age of 1.5 to 3.5 months) decreased anxiety and improved locomotor and exploratory behavior in OXYS rats. In untreated OXYS rats, MRI revealed an increase of the area of hippocampus, substantial hydrocephalus and 2-fold increased area of the lateral ventricles. Rapamycin treatment prevented these abnormalities, erasing the difference between OXYS and Wistar rats (used as control). All untreated OXYS rats showed signs of neurodegeneration, manifested by loci of demyelination. Rapamycin decreased the percentage of animals with demyelination and the number of loci. Levels of Tau and phospho-Tau (T181) were increased in OXYS rats (compared with Wistar). Rapamycin significantly decreased Tau and inhibited its phosphorylation in the hippocampus of OXYS and Wistar rats. Importantly, rapamycin treatment caused a compensatory increase in levels of S6 and correspondingly levels of phospo-S6 in the frontal cortex, indicating that some downstream events were compensatory preserved, explaining the lack of toxicity. We conclude that rapamycin in low chronic doses can suppress brain aging. PMID:23817674

  20. Accelerated aging of adhesive-mediated fiber post-resin composite bonds: A modeling approach.

    PubMed

    Radovic, Ivana; Monticelli, Francesca; Papacchini, Federica; Magni, Elisa; Cury, Alvaro Hafiz; Vulicevic, Zoran R; Ferrari, Marco

    2007-08-01

    Although fiber posts luted in root canals are not directly exposed to oral fluids, water storage is considered as in vitro accelerated aging test for bonded interfaces. The aim of the study was to evaluate the influence of accelerated water aging on fiber post-resin composite adhesion. Forty fiber posts (DT Light Post, RTD) were randomly divided into two main groups, according to the surface treatment performed. Group I: XPBond adhesive (Dentsply Caulk); Group II: sandblasting (Rocatec-Pre, 3M ESPE) and XPBond. Dual-cured resin cement (Calibra, Dentsply Caulk) and flowable composite (X-Flow, Dentsply Caulk) were applied on the posts to produce cylindrical specimens. The bond strength at the interface between post and cement/composite was measured with the microtensile test according to the non-trimming technique. Half of the sticks were tested immediately for bond strength, while in the other half testing was performed after 1 month of water storage at 37 degrees C. Post-cement/composite interfaces were evaluated under SEM prior and after water aging. Statistical analysis was performed using the Kruskal-Wallis ANOVA followed by Dunn's multiple range test (p<0.05). Immediate bond strength was higher on sandblasted posts. After water aging the two post surface treatments resulted comparable in bond strength. Resin cement achieved higher bond strength to fiber posts than flowable composite. Water aging significantly reduced bond strength. Sandblasting followed by adhesive coating may improve immediate post-resin bond strength in comparison to adhesive alone. However, fiber post-resin bond strength mediated by hydrophilic adhesive tends to decrease after water aging.

  1. Mouse models of ageing and their relevance to disease.

    PubMed

    Kõks, Sulev; Dogan, Soner; Tuna, Bilge Guvenc; González-Navarro, Herminia; Potter, Paul; Vandenbroucke, Roosmarijn E

    2016-12-01

    Ageing is a process that gradually increases the organism's vulnerability to death. It affects different biological pathways, and the underlying cellular mechanisms are complex. In view of the growing disease burden of ageing populations, increasing efforts are being invested in understanding the pathways and mechanisms of ageing. We review some mouse models commonly used in studies on ageing, highlight the advantages and disadvantages of the different strategies, and discuss their relevance to disease susceptibility. In addition to addressing the genetics and phenotypic analysis of mice, we discuss examples of models of delayed or accelerated ageing and their modulation by caloric restriction. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  2. Chronic skin inflammation accelerates macrophage cholesterol crystal formation and atherosclerosis

    PubMed Central

    Ng, Qimin; Sanda, Gregory E.; Dey, Amit K.; Teague, Heather L.; Sorokin, Alexander V.; Dagur, Pradeep K.; Silverman, Joanna I.; Harrington, Charlotte L.; Rodante, Justin A.; Rose, Shawn M.; Varghese, Nevin J.; Belur, Agastya D.; Goyal, Aditya; Gelfand, Joel M.; Springer, Danielle A.; Bleck, Christopher K.E.; Thomas, Crystal L.; Yu, Zu-Xi; Winge, Mårten C.G.; Kruth, Howard S.; Marinkovich, M. Peter; Joshi, Aditya A.; Playford, Martin P.; Mehta, Nehal N.

    2018-01-01

    Inflammation is critical to atherogenesis. Psoriasis is a chronic inflammatory skin disease that accelerates atherosclerosis in humans and provides a compelling model to understand potential pathways linking these diseases. A murine model capturing the vascular and metabolic diseases in psoriasis would accelerate our understanding and provide a platform to test emerging therapies. We aimed to characterize a new murine model of skin inflammation (Rac1V12) from a cardiovascular standpoint to identify novel atherosclerotic signaling pathways modulated in chronic skin inflammation. The RacV12 psoriasis mouse resembled the human disease state, including presence of systemic inflammation, dyslipidemia, and cardiometabolic dysfunction. Psoriasis macrophages had a proatherosclerotic phenotype with increased lipid uptake and foam cell formation, and also showed a 6-fold increase in cholesterol crystal formation. We generated a triple-genetic K14-RacV12–/+/Srb1–/–/ApoER61H/H mouse and confirmed psoriasis accelerates atherogenesis (~7-fold increase). Finally, we noted a 60% reduction in superoxide dismutase 2 (SOD2) expression in human psoriasis macrophages. When SOD2 activity was restored in macrophages, their proatherogenic phenotype reversed. We demonstrate that the K14-RacV12 murine model captures the cardiometabolic dysfunction and accelerates vascular disease observed in chronic inflammation and that skin inflammation induces a proatherosclerotic macrophage phenotype with impaired SOD2 function, which associated with accelerated atherogenesis. PMID:29321372

  3. Influence of artificial accelerated aging on the color stability and opacity of composites of different shades.

    PubMed

    Mundim, F M; Da Fonseca Roberti Garcia, L; Silva Sousa, A B; Cruvinel, D R; De Carvalho Panzeri Pires-De-Souza, F

    2010-10-01

    The aim of this study was to evaluate the influence of artificial accelerated aging on the color stability and opacity of composites of different shades. Four composites for direct use (Heliomolar, 4 Seasons, Tetric EvoCeram; QuiXfil) and one for indirect use (SR Adoro) in two shades were used: light (A2) and dark (C3 for direct, and D4 for indirect composite). QuiXfil was obtained in Universal shade. A Teflon matrix (12 X 2 mm) was used to obtain 54 specimens (N=6), which were submitted to color and opacity analysis (Spectrophotometer PCB 6807, Byk Gardner) before and after artificial accelerated aging for 384 hours. After the statistical analysis (2-way ANOVA - Bonferroni - P<0.05), significant color alteration was observed in the light and dark composites studied (P<0.05), with the exception of QuiXfil. Composite 4 Seasons/C3 showed less color alteration (ΔE=0.91). The opacity alteration (ΔOP) was higher for light composites. Artificial accelerated aging interfered in the optical properties assessed; however, the alterations seemed to be more related to the composites composition than to their shade.

  4. Evidence of accelerated aging among African Americans and its implications for mortality.

    PubMed

    Levine, M E; Crimmins, E M

    2014-10-01

    Blacks experience morbidity and mortality earlier in the life course compared to whites. Such premature declines in health may be indicative of an acceleration of the aging process. The current study uses data on 7644 black and white participants, ages 30 and above, from the third National Health and Nutrition Examination Survey, to compare the biological ages of blacks and whites as indicated from a combination of ten biomarkers and to determine if such differences in biological age relative to chronological age account for racial disparities in mortality. At a specified chronological age, blacks are approximately 3 years older biologically than whites. Differences in biological age between blacks and whites appear to increase up until ages 60-65 and then decline, presumably due to mortality selection. Finally, differences in biological age were found to completely account for higher levels of all-cause, cardiovascular and cancer mortality among blacks. Overall, these results suggest that being black is associated with significantly higher biological age at a given chronological age and that this is a pathway to early death both overall and from the major age-related diseases. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. 1,25-Dihydroxyvitamin D deficiency accelerates alveolar bone loss independent of aging and extracellular calcium and phosphorus.

    PubMed

    Gong, Aixiu; Chen, Jie; Wu, Jun; Li, Jing; Wang, Lin; Goltzman, David; Miao, Dengshun

    2018-04-10

    Vitamin D is critical for bone homeostasis and immunomodulation. We therefore assessed whether 1,25-dihydroxyvitamin D (1,25(OH) 2 D) deficiency in mice with targeted deletion of the gene encoding 25-hydroxyvitaminD-1αhydroxylase [1α(OH)ase] (1αOH)ase -/- mice) results in alveolar bone loss and periodontal inflammation in vivo. 10-week-old and 12-month-old 1α(OH)ase -/- mice and wild-type littermates were fed a normal diet or a rescue diet, and the phenotype of the periodontium was then analyzed using micro-computed tomography, histology, immunohistochemistry and real-time RT-PCR. Alveolar bone loss was increased and maxillary bone mineral density (BMD), osteoblast numbers and the number of osterix-positive cells were decreased significantly in 1α(OH)ase -/- mice compared with wild-type mice. Although aging from 10 weeks to 12 months accentuated these changes, and a rescue diet reduced them, the alterations in the 1α(OH)ase -/- mice exceeded the effects of aging and diet change. Nuclear factor kappa light-chain-enhancer of activated B cells (NF-кB) p65 and CD3 positive cells, and the gene expression levels of interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), matrix metalloproteinase (MMP) -3 and -8 were all increased significantly in periodontal tissues of 1α(OH)ase -/- mice compared with wild-type mice. Aging from 10 weeks to 12 months also accentuated these changes, and a rescue diet reduced them, however, the alterations in the 1α(OH)ase -/- mice exceeded the effects of aging and diet change. 1,25(OH) 2 D deficiency in the 1α(OH)ase -/- mice accelerated alveolar bone loss by inhibiting osteoblastic bone formation and enhancing periodontal tissue degeneration in a calcium and phosphorus as well as age independent manner. This article is protected by copyright. All rights reserved. © 2018 American Academy of Periodontology.

  6. How Reliable Are the Reported Genetic Associations in Disc Degeneration?: The Influence of Phenotypes, Age, Population Size, and Inclusion Sequence in 809 Patients.

    PubMed

    Rajasekaran, S; Kanna, Rishi Mugesh; Reddy, Ranjani Raja; Natesan, Senthil; Raveendran, Muthuraja; Cheung, Kenneth M C; Chan, Danny; Kao, Patrick Y P; Yee, Anita; Shetty, Ajoy Prasad

    2016-11-01

    Prospective genetic association study. The aim of this study was to document the variations in the genetic associations, when different magnetic resonance imaging (MRI) phenotypes, age stratification, cohort size, and sequence of cohort inclusion are varied in the same study population. Genetic associations with disc degeneration have shown high inconsistency, generally attributed to hereditary factors and ethnic variations. However, the effect of different phenotypes, size of the study population, age of the cohort, etc have not been documented clearly. Seventy-one single-nucleotide polymorphisms (SNPs) of 41 candidate genes were correlated to six MRI markers of disc degeneration (annular tears, Pfirmann grading, Schmorl nodes, Modic changes, Total Endplate Damage score, and disc bulge) in 809 patients with back pain and/or sciatica. In the same study group, the correlations were then retested for different age groups, different sample, size and sequence of subject inclusion (first 404 and the second 405) and the differences documented. The mean age of population (M: 455, F: 354) was 36.7 ± 10.8 years. Different genetic associations were found with different phenotypes: disc bulge with three SNPs of CILP; annular tears with rs2249350 of ADAMTS5 and rs11247361 IGF1R; modic changes with VDR and MMP20; Pfirmann grading with three SNPs of MMP20 and Schmorl node with SNPs of CALM1 and FN1 and none with Total End Plate Score.Subgroup analysis based on three age groups and dividing the total population into two groups also completely changed the associations for all the six radiographic parameters. In the same study population, SNP associations completely change with different phenotypes. Variations in age, inclusion sequence, and sample size resulted in change of genetic associations. Our study questions the validity of previous studies and necessitates the need for standardizing the description of disc degeneration, phenotype selection, study sample size, age, and

  7. The effect of copper, MDA, and accelerated aging on jet fuel thermal stability as measured by the gravimetric JFTOT

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Pande, S.G.; Hardy, D.R.

    1995-05-01

    Thermally unstable jet fuels pose operational problems. In order to adequately identify such fuels, factors that realistically impact on thermal stability were examined. Evaluation was based on a quantitative method of measuring thermal stability, viz., NRL`s recently developed gravimetric JFTOT. This method gives a quantitative measurement of both the strip deposit and filterables formed. The pertinent factors examined, included the individual and interactive effects of: soluble copper, MDA (metal deactivator), and aging. The latter was accelerated to simulate field conditions of approximately six months aging at ambient temperature and pressure. The results indicate that the individual and interactive effects ofmore » copper, MDA, and accelerated aging appear to be fuel dependent. Based on the results, the three test fuels examined (one JP-8 and two JP-5s) were categorized as exhibiting very good, typical, and poor thermal stabilities, respectively. For both the very good and poor thermal stability fuels, the effect of copper in conjunction with accelerated aging did not significantly increase the total thermal deposits of the neat fuels. In contrast, for the typical thermal stability fuel, the combined effects of copper and accelerated aging, did. Furthermore, the addition of MDA prior to aging of the copper-doped, typical stability fuel significantly counteracted the adverse effect of copper and aging. A similar beneficial effect of MDA was not observed for the poor stability fuel. These results focus on the compositional differences among fuels and the need to elucidate these differences (physical and chemical) for a better understanding and prediction of their performance.« less

  8. Nuclear lamina defects cause ATM-dependent NF-κB activation and link accelerated aging to a systemic inflammatory response

    PubMed Central

    Osorio, Fernando G.; Bárcena, Clea; Soria-Valles, Clara; Ramsay, Andrew J.; de Carlos, Félix; Cobo, Juan; Fueyo, Antonio; Freije, José M.P.; López-Otín, Carlos

    2012-01-01

    Alterations in the architecture and dynamics of the nuclear lamina have a causal role in normal and accelerated aging through both cell-autonomous and systemic mechanisms. However, the precise nature of the molecular cues involved in this process remains incompletely defined. Here we report that the accumulation of prelamin A isoforms at the nuclear lamina triggers an ATM- and NEMO-dependent signaling pathway that leads to NF-κB activation and secretion of high levels of proinflammatory cytokines in two different mouse models of accelerated aging (Zmpste24−/− and LmnaG609G/G609G mice). Causal involvement of NF-κB in accelerated aging was demonstrated by the fact that both genetic and pharmacological inhibition of NF-κB signaling prevents age-associated features in these animal models, significantly extending their longevity. Our findings provide in vivo proof of principle for the feasibility of pharmacological modulation of the NF-κB pathway to slow down the progression of physiological and pathological aging. PMID:23019125

  9. The effect of accelerated ageing on colour stability of visible light-cured (VLC) chairside denture liners.

    PubMed

    Kostoulas, Ioannis; Polyzois, Gregory; Mitsoudis, Anastasios; Kavoura, Victoria; Frangou, Maria

    2012-06-01

    The purpose of this study was to assess the colour stability of seven visible light-cured (VLC) hard and soft denture liners by an in vitro accelerated ageing test and compare them with two autopolymerised hard and soft liners. Ten specimens of each material were fabricated. The initial colour was measured with a tri-stimulus colorimeter. One set of five specimens was placed in distilled water at 37°C in the dark for 15 days, while the remaining were subjected to UV/visible light-accelerated ageing initially for 24 h and then for 144 h. Colour change (ΔΕ) was calculated. Data were statistically analysed by anova, Tukey and t-tests at α = 0.05. All the liners showed clinically acceptable colour change (ΔΕ ≤ 6.8) in distilled water. The colour changes after ageing for Triad DuaLine, Lightdon U, Ufi Gel H and Light Liner Hard were clinically unacceptable (ΔΕ ≥ 6.8), whereas LightLiner Soft, Astron LC Soft, Triad Resiline and Flexacryl Soft presented slighter and clinically acceptable colour change (ΔΕ ≤ 6.8). Accelerated ageing affected significantly the colour stability of all denture liners tested except Astron LC Soft. Soft VLC denture liners were more colour-stable than hard VLC liners. © 2011 The Gerodontology Society and John Wiley & Sons A/S.

  10. Parkin absence accelerates microtubule aging in dopaminergic neurons.

    PubMed

    Cartelli, Daniele; Amadeo, Alida; Calogero, Alessandra Maria; Casagrande, Francesca Vittoria Marialuisa; De Gregorio, Carmelita; Gioria, Mariarosa; Kuzumaki, Naoko; Costa, Ilaria; Sassone, Jenny; Ciammola, Andrea; Hattori, Nobutaka; Okano, Hideyuki; Goldwurm, Stefano; Roybon, Laurent; Pezzoli, Gianni; Cappelletti, Graziella

    2018-01-01

    Loss-of-function caused by mutations in the parkin gene (PARK2) lead to early-onset familial Parkinson's disease. Recently, mechanistic studies proved the ability of parkin in regulating mitochondria homeostasis and microtubule (MT) stability. Looking at these systems during aging of PARK2 knockout mice, we found that loss of parkin induced an accelerated (over)acetylation of MT system both in dopaminergic neuron cell bodies and fibers, localized in the substantia nigra and corpus striatum, respectively. Interestingly, in PARK2 knockout mice, changes of MT stability preceded the alteration of mitochondria transport. Moreover, in-cell experiments confirmed that loss of parkin affects mitochondria mobility and showed that this defect depends on MT system as it is rescued by paclitaxel, a well-known MT-targeted agent. Furthermore, both in PC12 neuronal cells and in patients' induced pluripotent stem cell-derived midbrain neurons, we observed that parkin deficiencies cause the fragmentation of stable MTs. Therefore, we suggest that parkin acts as a regulator of MT system during neuronal aging, and we endorse the hypothesis that MT dysfunction may be crucial in the pathogenesis of Parkinson's disease. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Deletion of Pofut1 in Mouse Skeletal Myofibers Induces Muscle Aging-Related Phenotypes in cis and in trans

    PubMed Central

    Zygmunt, Deborah A.; Singhal, Neha; Kim, Mi-Lyang; Cramer, Megan L.; Crowe, Kelly E.; Xu, Rui; Jia, Ying; Adair, Jessica; Martinez-Pena y Valenzuela, Isabel; Akaaboune, Mohammed; White, Peter; Janssen, Paulus M.

    2017-01-01

    ABSTRACT Sarcopenia, the loss of muscle mass and strength during normal aging, involves coordinate changes in skeletal myofibers and the cells that contact them, including satellite cells and motor neurons. Here we show that the protein O-fucosyltransferase 1 gene (Pofut1), which encodes a glycosyltransferase required for NotchR-mediated cell-cell signaling, has reduced expression in aging skeletal muscle. Moreover, premature postnatal deletion of Pofut1 in skeletal myofibers can induce aging-related phenotypes in cis within skeletal myofibers and in trans within satellite cells and within motor neurons via the neuromuscular junction. Changed phenotypes include reduced skeletal muscle size and strength, decreased myofiber size, increased slow fiber (type 1) density, increased muscle degeneration and regeneration in aged muscles, decreased satellite cell self-renewal and regenerative potential, and increased neuromuscular fragmentation and occasional denervation. Pofut1 deletion in skeletal myofibers reduced NotchR signaling in young adult muscles, but this effect was lost with age. Increasing muscle NotchR signaling also reduced muscle size. Gene expression studies point to regulation of cell cycle genes, muscle myosins, NotchR and Wnt pathway genes, and connective tissue growth factor by Pofut1 in skeletal muscle, with additional effects on α dystroglycan glycosylation. PMID:28265002

  12. Accumulated environmental risk determining age at schizophrenia onset: a deep phenotyping-based study.

    PubMed

    Stepniak, Beata; Papiol, Sergi; Hammer, Christian; Ramin, Anna; Everts, Sarah; Hennig, Lena; Begemann, Martin; Ehrenreich, Hannelore

    2014-11-01

    Schizophrenia is caused by a combination of genetic and environmental factors, as first evidenced by twin studies. Extensive efforts have been made to identify the genetic roots of schizophrenia, including large genome-wide association studies, but these yielded very small effect sizes for individual markers. In this study, we aimed to assess the relative contribution of genome-wide association study-derived genetic versus environmental risk factors to crucial determinants of schizophrenia severity: disease onset, disease severity, and socioeconomic measures. In this parallel analysis, we studied 750 male patients from the Göttingen Research Association for Schizophrenia (GRAS) dataset (Germany) with schizophrenia for whom both genome-wide coverage of single-nucleotide polymorphisms and deep clinical phenotyping data were available. Specifically, we investigated the potential effect of schizophrenia risk alleles as identified in the most recent large genome-wide association study versus the effects of environmental hazards (ie, perinatal brain insults, cannabis use, neurotrauma, psychotrauma, urbanicity, and migration), alone and upon accumulation, on age at disease onset, age at prodrome, symptom expression, and socioeconomic parameters. In this study, we could show that frequent environmental factors become a major risk for early schizophrenia onset when accumulated (prodrome begins up to 9 years earlier; p=2·9×10(-10)). In particular, cannabis use-an avoidable environmental risk factor-is highly significantly associated with earlier age at prodrome (p=3·8×10(-20)). By contrast, polygenic genome-wide association study risk scores did not have any detectable effects on schizophrenia phenotypes. These findings should be translated to preventive measures to reduce environmental risk factors, since age at onset of schizophrenia is a crucial determinant of an affected individual's fate and the total socioeconomic cost of the illness. German Research Foundation

  13. Reproducing ten years of road ageing--accelerated carbonation and leaching of EAF steel slag.

    PubMed

    Suer, Pascal; Lindqvist, Jan-Erik; Arm, Maria; Frogner-Kockum, Paul

    2009-09-01

    Reuse of industrial aggregates is still hindered by concern for their long-term properties. This paper proposes a laboratory method for accelerated ageing of steel slag, to predict environmental and technical properties, starting from fresh slag. Ageing processes in a 10-year old asphalt road with steel slag of electric arc furnace (EAF) type in the subbase were identified by scanning electron microscopy (SEM) and leaching tests. Samples from the road centre and the pavement edge were compared with each other and with samples of fresh slag. It was found that slag from the pavement edge showed traces of carbonation and leaching processes, whereas the road centre material was nearly identical to fresh slag, in spite of an accessible particle structure. Batches of moisturized road centre material exposed to oxygen, nitrogen or carbon dioxide (CO2) were used for accelerated ageing. Time (7-14 days), temperature (20-40 degrees C) and initial slag moisture content (8-20%) were varied to achieve the carbonation (decrease in pH) and leaching that was observed in the pavement edge material. After ageing, water was added to assess leaching of metals and macroelements. 12% moisture, CO2 and seven days at 40 degrees C gave the lowest pH value. This also reproduced the observed ageing effect for Ca, Cu, Ba, Fe, Mn, Pb, Ca (decreased leaching) and for V, Si, and Al (increased leaching). However, ageing effects on SO4, DOC and Cr were not reproduced.

  14. Shift from slow- to fast-water habitats accelerates lineage and phenotype evolution in a clade of Neotropical suckermouth catfishes (Loricariidae: Hypoptopomatinae).

    PubMed

    Roxo, Fábio F; Lujan, Nathan K; Tagliacollo, Victor A; Waltz, Brandon T; Silva, Gabriel S C; Oliveira, Claudio; Albert, James S

    2017-01-01

    Identifying habitat characteristics that accelerate organismal evolution is essential to understanding both the origins of life on Earth and the ecosystem properties that are most critical to maintaining life into the future. Searching for these characteristics on a large scale has only recently become possible via advances in phylogenetic reconstruction, time-calibration, and comparative analyses. In this study, we combine these tools with habitat and phenotype data for 105 species in a clade of Neotropical suckermouth catfishes commonly known as cascudinhos. Our goal was to determine whether riverine mesohabitats defined by different flow rates (i.e., pools vs. rapids) and substrates (plants vs. rocks) have affected rates of cascudinho cladogenesis and morphological diversification. In contrast to predictions based on general theory related to life in fast-flowing, rocky riverine habitats, Neoplecostomini lineages associated with these habitats exhibited increased body size, head shape diversity, and lineage and phenotype diversification rates. These findings are consistent with a growing understanding of river rapids as incubators of biological diversification and specialization. They also highlight the urgent need to conserve rapids habitats throughout the major rivers of the world.

  15. Circadian disruption induced by light-at-night accelerates aging and promotes tumorigenesis in rats

    PubMed Central

    Vinogradova, Irina A.; Anisimov, Vladimir N.; Bukalev, Andrey V.; Semenchenko, Anna V.; Zabezhinski, Mark A.

    2009-01-01

    We evaluated the effect of various light/dark regimens on the survival, life span and tumorigenesis in rats. Two hundred eight male and 203 females LIO rats were subdivided into 4 groups and kept at various light/dark regimens: standard 12:12 light/dark (LD); natural lighting of the North-West of Russia (NL); constant light (LL), and constant darkness (DD) since the age of 25 days until natural death. We found that exposure to NL and LL regimens accelerated development of metabolic syndrome and spontaneous tumorigenesis, shortened life span both in male and females rats as compared to the standard LD regimen. We conclude that circadian disruption induced by light-at-night accelerates aging and promotes tumorigenesis in rats. This observation supports the conclusion of the International Agency Research on Cancer that shift-work that involves circadian disruption is probably carcinogenic to humans. PMID:20157558

  16. Super-Resolution of Plant Disease Images for the Acceleration of Image-based Phenotyping and Vigor Diagnosis in Agriculture.

    PubMed

    Yamamoto, Kyosuke; Togami, Takashi; Yamaguchi, Norio

    2017-11-06

    Unmanned aerial vehicles (UAVs or drones) are a very promising branch of technology, and they have been utilized in agriculture-in cooperation with image processing technologies-for phenotyping and vigor diagnosis. One of the problems in the utilization of UAVs for agricultural purposes is the limitation in flight time. It is necessary to fly at a high altitude to capture the maximum number of plants in the limited time available, but this reduces the spatial resolution of the captured images. In this study, we applied a super-resolution method to the low-resolution images of tomato diseases to recover detailed appearances, such as lesions on plant organs. We also conducted disease classification using high-resolution, low-resolution, and super-resolution images to evaluate the effectiveness of super-resolution methods in disease classification. Our results indicated that the super-resolution method outperformed conventional image scaling methods in spatial resolution enhancement of tomato disease images. The results of disease classification showed that the accuracy attained was also better by a large margin with super-resolution images than with low-resolution images. These results indicated that our approach not only recovered the information lost in low-resolution images, but also exerted a beneficial influence on further image analysis. The proposed approach will accelerate image-based phenotyping and vigor diagnosis in the field, because it not only saves time to capture images of a crop in a cultivation field but also secures the accuracy of these images for further analysis.

  17. Fisetin Reduces the Impact of Aging on Behavior and Physiology in the Rapidly Aging SAMP8 Mouse.

    PubMed

    Currais, Antonio; Farrokhi, Catherine; Dargusch, Richard; Armando, Aaron; Quehenberger, Oswald; Schubert, David; Maher, Pamela

    2018-03-02

    Alzheimer's disease (AD) is rarely addressed in the context of aging even though there is an overlap in pathology. We previously used a phenotypic screening platform based on old age-associated brain toxicities to identify the flavonol fisetin as a potential therapeutic for AD and other age-related neurodegenerative diseases. Based on earlier results with fisetin in transgenic AD mice, we hypothesized that fisetin would be effective against brain aging and cognitive dysfunction in rapidly aging senescence-accelerated prone 8 (SAMP8) mice, a model for sporadic AD and dementia. An integrative approach was used to correlate protein expression and metabolite levels in the brain with cognition. It was found that fisetin reduced cognitive deficits in old SAMP8 mice while restoring multiple markers associated with impaired synaptic function, stress, and inflammation. These results provide further evidence for the potential benefits of fisetin for the treatment of age-related neurodegenerative diseases.

  18. Transgenic expression of cyclooxygenase-2 (COX2) causes premature aging phenotypes in mice.

    PubMed

    Kim, Joohwee; Vaish, Vivek; Feng, Mingxiao; Field, Kevin; Chatzistamou, Ioulia; Shim, Minsub

    2016-10-07

    Cyclooxygenase (COX) is a key enzyme in the biosynthesis of prostanoids, lipid signaling molecules that regulate various physiological processes. COX2, one of the isoforms of COX, is highly inducible in response to a wide variety of cellular and environmental stresses. Increased COX2 expression is thought to play a role in the pathogenesis of many age-related diseases. COX2 expression is also reported to be increased in the tissues of aged humans and mice, which suggests the involvement of COX2 in the aging process. However, it is not clear whether the increased COX2 expression is causal to or a result of aging. We have now addressed this question by creating an inducible COX2 transgenic mouse model. Here we show that post-natal expression of COX2 led to a panel of aging-related phenotypes. The expression of p16, p53, and phospho-H2AX was increased in the tissues of COX2 transgenic mice. Additionally, adult mouse lung fibroblasts from COX2 transgenic mice exhibited increased expression of the senescence-associated β-galactosidase. Our study reveals that the increased COX2 expression has an impact on the aging process and suggests that modulation of COX2 and its downstream signaling may be an approach for intervention of age-related disorders.

  19. Ageing induced vascular smooth muscle cell senescence in atherosclerosis.

    PubMed

    Uryga, Anna K; Bennett, Martin R

    2016-04-15

    Atherosclerosis is a disease of ageing in that its incidence and prevalence increase with age. However, atherosclerosis is also associated with biological ageing, manifest by a number of typical hallmarks of ageing in the atherosclerotic plaque. Thus, accelerated biological ageing may be superimposed on the effects of chronological ageing in atherosclerosis. Tissue ageing is seen in all cells that comprise the plaque, but particularly in vascular smooth muscle cells (VSMCs). Hallmarks of ageing include evidence of cell senescence, DNA damage (including telomere attrition), mitochondrial dysfunction, a pro-inflammatory secretory phenotype, defects in proteostasis, epigenetic changes, deregulated nutrient sensing, and exhaustion of progenitor cells. In this model, initial damage to DNA (genomic, telomeric, mitochondrial and epigenetic changes) results in a number of cellular responses (cellular senescence, deregulated nutrient sensing and defects in proteostasis). Ultimately, ongoing damage and attempts at repair by continued proliferation overwhelm reparative capacity, causing loss of specialised cell functions, cell death and inflammation. This review summarises the evidence for accelerated biological ageing in atherosclerosis, the functional consequences of cell ageing on cells comprising the plaque, and the causal role that VSMC senescence plays in atherogenesis. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

  20. Resin composite characterizations following a simplified protocol of accelerated aging as a function of the expiration date.

    PubMed

    D'Alpino, Paulo Henrique Perlatti; Vismara, Marcus Vinícius Gonçalves; Mello, Luciano Marcelo de Medeiros; Di Hipólito, Vinicius; González, Alejandra Hortencia Miranda; Graeff, Carlos Frederico de Oliveira

    2014-07-01

    This study evaluated the mechanical, thermal, and morphological characteristics of different classifications of dental composites as a function of the material condition (new, aged and expired). Specimens were obtained according to these factors: Composites: Filtek P60, Filtek Z250, Filtek Z350XT, and Filtek Silorane; and Material conditions: new, aged, and expired. The syringe composites underwent an accelerated aging protocol (Arrhenius model). The flexural strength (FS) and flexural modulus (E) were obtained. The thermogravimetric analysis (TGA) and differential thermal analysis (DTA) were also performed and the glass transition temperature (Tg) and the weight loss calculated. Topographic analysis of the composites was performed under SEM. The material conditions influenced the mechanical properties of the composites. The silorane composite exhibited a characteristic thermal behavior different from that of the methacrylates. In general, the Tg increased after the accelerated aging protocol and decreased for expired ones, compared to the new composites. A significant increase in FS of Filtek Z350XT after aging was accompanied by an increase in the Tg. The filler packings were in accordance with the manufacture׳s information. The topographic aspects of the composites were modified as a function of the material condition. The mechanical properties of the composites following a simplified protocol of accelerated aging varied as a function of the expiration date. The silorane composite presented a characteristic thermal behavior. Although the dental manufacturers may not be able to control variables as storage temperature and transportation conditions, these effects on the composite clinical performance can be minimized if properly considered. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age

    PubMed Central

    Xu, Ming; Tchkonia, Tamara; Ding, Husheng; Ogrodnik, Mikolaj; Lubbers, Ellen R.; Pirtskhalava, Tamar; White, Thomas A.; Johnson, Kurt O.; Stout, Michael B.; Mezera, Vojtech; Giorgadze, Nino; Jensen, Michael D.; LeBrasseur, Nathan K.; Kirkland, James L.

    2015-01-01

    Chronic, low grade, sterile inflammation frequently accompanies aging and age-related diseases. Cellular senescence is associated with the production of proinflammatory chemokines, cytokines, and extracellular matrix (ECM) remodeling proteases, which comprise the senescence-associated secretory phenotype (SASP). We found a higher burden of senescent cells in adipose tissue with aging. Senescent human primary preadipocytes as well as human umbilical vein endothelial cells (HUVECs) developed a SASP that could be suppressed by targeting the JAK pathway using RNAi or JAK inhibitors. Conditioned medium (CM) from senescent human preadipocytes induced macrophage migration in vitro and inflammation in healthy adipose tissue and preadipocytes. When the senescent cells from which CM was derived had been treated with JAK inhibitors, the resulting CM was much less proinflammatory. The administration of JAK inhibitor to aged mice for 10 wk alleviated both adipose tissue and systemic inflammation and enhanced physical function. Our findings are consistent with a possible contribution of senescent cells and the SASP to age-related inflammation and frailty. We speculate that SASP inhibition by JAK inhibitors may contribute to alleviating frailty. Targeting the JAK pathway holds promise for treating age-related dysfunction. PMID:26578790

  2. Genetic and environmental influences on skeletal muscle phenotypes as a function of age and sex in large, multigenerational families of African heritage.

    PubMed

    Prior, Steven J; Roth, Stephen M; Wang, Xiaojing; Kammerer, Candace; Miljkovic-Gacic, Iva; Bunker, Clareann H; Wheeler, Victor W; Patrick, Alan L; Zmuda, Joseph M

    2007-10-01

    The aim of this study was to estimate the heritability of and environmental contributions to skeletal muscle phenotypes (appendicular lean mass and calf muscle cross-sectional area) in subjects of African descent and to determine whether heritability estimates are impacted by sex or age. Body composition was measured by dual-energy X-ray absorptiometry and computed tomography in 444 men and women aged 18 yr and older (mean: 43 yr) from eight large, multigenerational Afro-Caribbean families (family size range: 21-112). Using quantitative genetic methods, we estimated heritability and the association of anthropometric, lifestyle, and medical variables with skeletal muscle phenotypes. In the overall group, we estimated the heritability of lean mass and calf muscle cross-sectional area (h(2) = 0.18-0.23, P < 0.01) and contribution of environmental factors to these phenotypes (r(2) = 0.27-0.55, P < 0.05). In our age-specific analysis, the heritability of leg lean mass was lower in older vs. younger individuals (h(2) = 0.05 vs. 0.23, respectively, P = 0.1). Sex was a significant covariate in our models (P < 0.001), although sex-specific differences in heritability varied depending on the lean mass phenotype analyzed. High genetic correlations (rho(G) = 0.69-0.81; P < 0.01) between different lean mass measures suggest these traits share a large proportion of genetic components. Our results demonstrate the heritability of skeletal muscle traits in individuals of African heritage and that heritability may differ as a function of sex and age. As the loss of skeletal muscle mass is related to metabolic abnormalities, disability, and mortality in older individuals, further research is warranted to identify specific genetic loci that contribute to these traits in general and in a sex- and age-specific manner.

  3. [The battery of tests for behavioral phenotyping of aging animals in the experiment].

    PubMed

    Gorina, Ya V; Komleva, Yu K; Lopatina, O L; Volkova, V V; Chernykh, A I; Shabalova, A A; Semenchukov, A A; Olovyannikova, R Ya; Salmina, A B

    2017-01-01

    The purpose of the study was to develop a battery of tests to study social and cognitive impairments for behavioral phenotyping of aging experimental animals with physiological neurodegeneration. Object of the study were outbred CD1 mice in the following groups: 1st group - 12-month old male mice (physiological aging); 2nd group - 2-month old male mice (control group). Social recognition test, elevated plus maze test (EPM), open field test, light-dark box test, and Fear conditioning protocol were used to estimate the neurological status of experimental animals. We found that aging male mice in a contrast to young ones have demonstrated lower social interest to female mice in the social recognition task. EPM and light-dark box tests showed increased level of anxiety in the group of aged mice comparing to the control group. Fear conditioning protocol revealed impairment of associative learning and memory in the group of aged mice, particularly, fear memory consolidation was dramatically suppressed. Analysis of behavioral factors, social interactions and anxiety level in the experimental mice has confirmed age-related neurodegeneration in the 1st group. We found that the most informative approach to identifying neurological impairments in aging mice (social interaction deficit, limitation of interests, increased level of anxiety) should be based on the open field test light-dark box test, and Fear conditioning protocol. Such combination allows obtaining new data on behavioral alterations in the age-associated of neurodegeneration and to develop novel therapeutic strategies for the treatment of age-related brain pathology.

  4. Pro‐arrhythmic atrial phenotypes in incrementally paced murine Pgc1β −/− hearts: effects of age

    PubMed Central

    Valli, Haseeb; Ahmad, Shiraz; Fraser, James A.; Jeevaratnam, Kamalan

    2017-01-01

    New Findings What is the central question of this study? Can we experimentally replicate atrial pro‐arrhythmic phenotypes associated with important chronic clinical conditions, including physical inactivity, obesity, diabetes mellitus and metabolic syndrome, compromising mitochondrial function, and clarify their electrophysiological basis? What is the main finding and its importance? Electrocardiographic and intracellular cardiomyocyte recording at progressively incremented pacing rates demonstrated age‐dependent atrial arrhythmic phenotypes in Langendorff‐perfused murine Pgc1β −/− hearts for the first time. We attributed these to compromised action potential conduction and excitation wavefronts, whilst excluding alterations in recovery properties or temporal electrophysiological instabilities, clarifying these pro‐arrhythmic changes in chronic metabolic disease. Atrial arrhythmias, most commonly manifesting as atrial fibrillation, represent a major clinical problem. The incidence of atrial fibrillation increases with both age and conditions associated with energetic dysfunction. Atrial arrhythmic phenotypes were compared in young (12–16 week) and aged (>52 week) wild‐type (WT) and peroxisome proliferative activated receptor, gamma, coactivator 1 beta (Ppargc1b)‐deficient (Pgc1β −/−) Langendorff‐perfused hearts, previously used to model mitochondrial energetic disorder. Electrophysiological explorations were performed using simultaneous whole‐heart ECG and intracellular atrial action potential (AP) recordings. Two stimulation protocols were used: an S1S2 protocol, which imposed extrasystolic stimuli at successively decremented intervals following regular pulse trains; and a regular pacing protocol at successively incremented frequencies. Aged Pgc1β −/− hearts showed greater atrial arrhythmogenicity, presenting as atrial tachycardia and ectopic activity. Maximal rates of AP depolarization (dV/dt max) were reduced in Pgc1β

  5. Genetic and pharmacological evidence that G2019S LRRK2 confers a hyperkinetic phenotype, resistant to motor decline associated with aging

    PubMed Central

    Longo, Francesco; Russo, Isabella; Shimshek, Derya R.; Greggio, Elisa; Morari, Michele

    2014-01-01

    The leucine-rich repeat kinase 2 mutation G2019S in the kinase-domain is the most common genetic cause of Parkinson's disease. To investigate the impact of the G2019S mutation on motor activity in vivo, a longitudinal phenotyping approach was developed in knock-in (KI) mice bearing this kinase-enhancing mutation. Two cohorts of G2019S KI mice and wild-type littermates (WT) were subjected to behavioral tests, specific for akinesia, bradykinesia and overall gait ability, at different ages (3, 6, 10, 15 and 19 months). The motor performance of G2019S KI mice remained stable up to the age of 19 months and did not show the typical age-related decline in immobility time and stepping activity of WT. Several lines of evidence suggest that enhanced LRRK2 kinase activity is the main contributor to the observed hyperkinetic phenotype of G2019S KI mice: i) KI mice carrying a LRRK2 kinase-dead mutation (D1994S KD) showed a similar progressive motor decline as WT; ii) two LRRK2 kinase inhibitors, H-1152 and Nov-LRRK2-11, acutely reversed the hyperkinetic phenotype of G2019S KI mice, while being ineffective in WT or D1994S KD animals. LRRK2 target engagement in vivo was further substantiated by reduction of LRRK2 phosphorylation at Ser935 in the striatum and cortex at efficacious doses of Nov-LRRK2-11, and in the striatum at efficacious doses of H-1152. In summary, expression of the G2019S mutation in the mouse LRRK2 gene confers a hyperkinetic phenotype that is resistant to age-related motor decline, likely via enhancement of LRRK2 kinase activity. This study provides an in vivo model to investigate the effects of LRRK2 inhibitors on motor function. PMID:25107341

  6. Effect of accelerated ageing and surface sealing on the permanent deformation of auto-polymerising soft linings.

    PubMed

    da Silva, Joaquim; Takahashi, Jessica; Nuňez, Juliana; Consani, Rafael; Mesquita, Marcelo

    2012-09-01

    To compare the effects of different ageing methods on the permanent deformation of two permanent soft liners. The materials selected were auto-polymerising acrylic resin and silicone-based reliners. Sealer coating was also evaluated. Sixty specimens of each reliner were manufactured (12.7 mm diameter and 19 mm length). Specimens were randomly distributed into 12 groups (n = 10) and submitted to one of the accelerated ageing processes. Permanent deformation tests were conducted with a mechanical device described within the American Dental Association specification number 18 with a compressive load of 750 gf applied for 30 s. All data were submitted for statistical analysis. Mann-Whitney test compared the effect of the surface sealer on each material and the permanent deformation of the materials in the same ageing group (p = 0.05). Kruskal-Wallis and Dunn tests compared all ageing groups of each material (p = 0.05). The silicone-based reliner presented a lower permanent deformation than the acrylic resin-based reliner, regardless of the ageing procedure. The surface sealer coating was effective only for the thermocycled silicone group and the accelerated ageing processes affected only the permanent deformation of the acrylic resin-based material. The silicone-based reliner presented superior elastic properties and the thermocycling was more effective in ageing the materials. © 2010 The Gerodontology Society and John Wiley & Sons A/S.

  7. Super-Resolution of Plant Disease Images for the Acceleration of Image-based Phenotyping and Vigor Diagnosis in Agriculture

    PubMed Central

    Togami, Takashi; Yamaguchi, Norio

    2017-01-01

    Unmanned aerial vehicles (UAVs or drones) are a very promising branch of technology, and they have been utilized in agriculture—in cooperation with image processing technologies—for phenotyping and vigor diagnosis. One of the problems in the utilization of UAVs for agricultural purposes is the limitation in flight time. It is necessary to fly at a high altitude to capture the maximum number of plants in the limited time available, but this reduces the spatial resolution of the captured images. In this study, we applied a super-resolution method to the low-resolution images of tomato diseases to recover detailed appearances, such as lesions on plant organs. We also conducted disease classification using high-resolution, low-resolution, and super-resolution images to evaluate the effectiveness of super-resolution methods in disease classification. Our results indicated that the super-resolution method outperformed conventional image scaling methods in spatial resolution enhancement of tomato disease images. The results of disease classification showed that the accuracy attained was also better by a large margin with super-resolution images than with low-resolution images. These results indicated that our approach not only recovered the information lost in low-resolution images, but also exerted a beneficial influence on further image analysis. The proposed approach will accelerate image-based phenotyping and vigor diagnosis in the field, because it not only saves time to capture images of a crop in a cultivation field but also secures the accuracy of these images for further analysis. PMID:29113104

  8. Effects of paternal phenotype and environmental variability on age and size at maturity in a male dimorphic mite

    NASA Astrophysics Data System (ADS)

    Smallegange, Isabel M.

    2011-04-01

    Investigating how the environment affects age and size at maturity of individuals is crucial to understanding how changes in the environment affect population dynamics through the biology of a species. Paternal phenotype, maternal, and offspring environment may crucially influence these traits, but to my knowledge, their combined effects have not yet been tested. Here, I found that in bulb mites ( Rhizoglyphus robini), maternal nutrition, offspring nutrition, and paternal phenotype (males are fighters, able to kill other mites, or benign scramblers) interactively affected offspring age and size at maturity. The largest effect occurred when both maternal and offspring nutrition was poor: in that case offspring from fighter sires required a significantly longer development time than offspring from scrambler sires. Investigating parental effects on the relationship between age and size at maturity revealed no paternal effects, and only for females was its shape influenced by maternal nutrition. Overall, this reaction norm was nonlinear. These non-genetic intergenerational effects may play a complex, yet unexplored role in influencing population fluctuations—possibly explaining why results from field studies often do not match theoretical predictions on maternal effects on population dynamics.

  9. The emerging role of alternative splicing in senescence and aging.

    PubMed

    Deschênes, Mathieu; Chabot, Benoit

    2017-10-01

    Deregulation of precursor mRNA splicing is associated with many illnesses and has been linked to age-related chronic diseases. Here we review recent progress documenting how defects in the machinery that performs intron removal and controls splice site selection contribute to cellular senescence and organismal aging. We discuss the functional association linking p53, IGF-1, SIRT1, and ING-1 splice variants with senescence and aging, and review a selection of splicing defects occurring in accelerated aging (progeria), vascular aging, and Alzheimer's disease. Overall, it is becoming increasingly clear that changes in the activity of splicing factors and in the production of key splice variants can impact cellular senescence and the aging phenotype. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  10. Distinctive Risk Factors and Phenotype of Younger Patients With Resistant Hypertension: Age Is Relevant.

    PubMed

    Ghazi, Lama; Oparil, Suzanne; Calhoun, David A; Lin, Chee Paul; Dudenbostel, Tanja

    2017-05-01

    Resistant hypertension, defined as blood pressure >140/90 mm Hg despite using ≥3 antihypertensive medications, is a well-recognized clinical entity. Patients with resistant hypertension are at an increased risk of cardiovascular disease compared with those with more easily controlled hypertension. Coronary heart disease mortality rates of younger adults are stagnating or on the rise. The purpose of our study was to characterize the phenotype and risk factors of younger patients with resistant hypertension, given the dearth of data on cardiovascular risk profile in this cohort. We conducted a cross-sectional analysis with predefined age groups of a large, ethnically diverse cohort of 2170 patients referred to the Hypertension Clinic at the University of Alabama at Birmingham. Patients (n=2068) met the inclusion criteria and were classified by age groups, that is, ≤40 years (12.7% of total cohort), 41 to 55 years (32.1%), 56 to 70 years (36.1%), and ≥71 years (19.1%). Patients aged ≤40 years compared with those aged ≥71 years had significantly earlier onset of hypertension (24.7±7.4 versus 55.0±14.1 years; P <0.0001), higher rates of obesity (53.4% versus 26.9%; P <0.0001), and significantly higher levels of plasma aldosterone (11.3±9.8 versus 8.9±7.4 ng/dL; P =0.005), plasma renin activity (4.9±10.2 versus 2.5±5.0 ng/mL per hour; P =0.001), 24-hour urinary aldosterone (13.4±10.0 versus 8.2±6.2 µg/24 h; P <0.0001), and sodium excretion (195.9±92.0 versus 146.8±67.1 mEq/24 h; P <0.0001). Among patients with resistant hypertension, younger individuals have a distinct phenotype characterized by overlapping risk factors and comorbidities, including obesity, high aldosterone, and high dietary sodium intake compared with elderly. © 2017 American Heart Association, Inc.

  11. THE ACCELERATION OF THE AGING PROCESS OF ALCOHOLIC BEVERAGES BY $gamma$- IRRADIATION

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Sumiki, Y.

    Using gamma irradiation, the aging of alcoholic beverages can be accelerated. Plain Japanese sake can be aged within l hr with a Co/sup 60/ source of 270 c (total dose l0,000 r). The taste and flavor of fresh sake can be improved with a few thousand r irr-adiation. The unpleasant flavor of poor grade sake and the yeast taste of new sake can be eliminated by irradiation. For natur-ally aged sake and compound sake, the change was very little for a dosage of l0,000 r, and beyond this limit the irradiated sakes were over-aged. For both aged sake and newmore » sake, undesirable tastes were detected for an irradiation dosage greater than 20,000 r. When the dosage approached l00,000 r, the typical irradiation odor'' was detected. Therefore, the ideal dosage range is from several thousand r to l04 r. At an irradiation dosage of l0,000 r, whisky and brandy were aged r-apidly. However, the color was somewhat faded. Distilled Japanese sakes were improved by ir-radiation, but excess irradiation caused undesirable aldehyde odors. (OID)« less

  12. Front acceleration by dynamic selection in Fisher population waves

    NASA Astrophysics Data System (ADS)

    Bénichou, O.; Calvez, V.; Meunier, N.; Voituriez, R.

    2012-10-01

    We introduce a minimal model of population range expansion in which the phenotypes of individuals present no selective advantage and differ only in their diffusion rate. We show that such neutral phenotypic variability (i.e., that does not modify the growth rate) alone can yield phenotype segregation at the front edge, even in absence of genetic noise, and significantly impact the dynamical properties of the expansion wave. We present an exact asymptotic traveling wave solution and show analytically that phenotype segregation accelerates the front propagation. The results are compatible with field observations such as invasions of cane toads in Australia or bush crickets in Britain.

  13. Nuclear DNA methylation and chromatin condensation phenotypes are distinct between normally proliferating/aging, rapidly growing/immortal, and senescent cells.

    PubMed

    Oh, Jin Ho; Gertych, Arkadiusz; Tajbakhsh, Jian

    2013-03-01

    This study reports on probing the utility of in situ chromatin texture features such as nuclear DNA methylation and chromatin condensation patterns - visualized by fluorescent staining and evaluated by dedicated three-dimensional (3D) quantitative and high-throughput cell-by-cell image analysis - in assessing the proliferative capacity, i.e. growth behavior of cells: to provide a more dynamic picture of a cell population with potential implications in basic science, cancer diagnostics/prognostics and therapeutic drug development. Two types of primary cells and four different cancer cell lines were propagated and subjected to cell-counting, flow cytometry, confocal imaging, and 3D image analysis at various points in culture. Additionally a subset of primary and cancer cells was accelerated into senescence by oxidative stress. DNA methylation and chromatin condensation levels decreased with declining doubling times when primary cells aged in culture with the lowest levels reached at the stage of proliferative senescence. In comparison, immortal cancer cells with constant but higher doubling times mostly displayed lower and constant levels of the two in situ-derived features. However, stress-induced senescent primary and cancer cells showed similar levels of these features compared with primary cells that had reached natural growth arrest. With regards to global DNA methylation and chromatin condensation levels, aggressively growing cancer cells seem to take an intermediate level between normally proliferating and senescent cells. Thus, normal cells apparently reach cancer-cell equivalent stages of the two parameters at some point in aging, which might challenge phenotypic distinction between these two types of cells. Companion high-resolution molecular profiling could provide information on possible underlying differences that would explain benign versus malign cell growth behaviors.

  14. IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging.

    PubMed

    Toth, Peter; Tarantini, Stefano; Ashpole, Nicole M; Tucsek, Zsuzsanna; Milne, Ginger L; Valcarcel-Ares, Noa M; Menyhart, Akos; Farkas, Eszter; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan

    2015-12-01

    Aging is associated with marked deficiency in circulating IGF-1, which has been shown to contribute to age-related cognitive decline. Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is thought to play a critical role in the genesis of age-related cognitive impairment. To establish the link between IGF-1 deficiency and cerebromicrovascular impairment, neurovascular coupling mechanisms were studied in a novel mouse model of IGF-1 deficiency (Igf1(f/f) -TBG-Cre-AAV8) and accelerated vascular aging. We found that IGF-1-deficient mice exhibit neurovascular uncoupling and show a deficit in hippocampal-dependent spatial memory test, mimicking the aging phenotype. IGF-1 deficiency significantly impaired cerebromicrovascular endothelial function decreasing NO mediation of neurovascular coupling. IGF-1 deficiency also impaired glutamate-mediated CBF responses, likely due to dysregulation of astrocytic expression of metabotropic glutamate receptors and impairing mediation of CBF responses by eicosanoid gliotransmitters. Collectively, we demonstrate that IGF-1 deficiency promotes cerebromicrovascular dysfunction and neurovascular uncoupling mimicking the aging phenotype, which are likely to contribute to cognitive impairment. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  15. Signaling pathway activation drift during aging: Hutchinson-Gilford Progeria Syndrome fibroblasts are comparable to normal middle-age and old-age cells.

    PubMed

    Aliper, Alexander M; Csoka, Antonei Benjamin; Buzdin, Anton; Jetka, Tomasz; Roumiantsev, Sergey; Moskalev, Alexy; Zhavoronkov, Alex

    2015-01-01

    For the past several decades, research in understanding the molecular basis of human aging has progressed significantly with the analysis of premature aging syndromes. Progerin, an altered form of lamin A, has been identified as the cause of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), and may be a contributing causative factor in normal aging. However, the question of whether HGPS actually recapitulates the normal aging process at the cellular and organismal level, or simply mimics the aging phenotype is widely debated. In the present study we analyzed publicly available microarray datasets for fibroblasts undergoing cellular aging in culture, as well as fibroblasts derived from young, middle-age, and old-age individuals, and patients with HGPS. Using GeroScope pathway analysis and drug discovery platform we analyzed the activation states of 65 major cellular signaling pathways. Our analysis reveals that signaling pathway activation states in cells derived from chronologically young patients with HGPS strongly resemble cells taken from normal middle-aged and old individuals. This clearly indicates that HGPS may truly represent accelerated aging, rather than being just a simulacrum. Our data also points to potential pathways that could be targeted to develop drugs and drug combinations for both HGPS and normal aging.

  16. Early age strength increase of fly ash blended cement by a ternary hardening accelerating admixture

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hoang, Kien; Justnes, Harald; SINTEF Building and Infrastructure

    The applicability of a combination of sodium thiocyanate (NaSCN), diethanolamine (DEA) and glycerol (Gly) with small dosages as a ternary hardening accelerating admixture for fly ash blended cement (OPC-FA) was studied. The ternary admixture induced higher early and later age mortar strength at both low (5 °C) and normal (20 °C) temperature. Despite used in lower dosage the ternary admixture led to higher strength of the investigated OPC-FA system than other chemicals (e.g. sodium sulfate). Results obtained from isothermal calorimetry, thermogravimetric analysis (TGA) and X-ray diffraction (XRD) showed that the ternary admixture accelerated the cement hydration and increased the amountmore » of AFm (notably calcium hemicarboaluminate hydrate) in the hydration products. A synergistic effect between the three components of the accelerator on the hydration of OPC-FA system was observed.« less

  17. Influence of surface sealing on color stability and roughness of composite submitted to ultraviolet-accelerated aging.

    PubMed

    Catelan, Anderson; Suzuki, Thaís Yumi Umeda; Becker, Francisco; Briso, André Luiz Fraga; Dos Santos, Paulo Henrique

    2017-05-01

    In the present study, we evaluated the influence of surface sealing on color stability and surface roughness of a composite resin after accelerated artificial aging. Thirty-two specimens of a composite were prepared. After 24 h, the specimens were polished and divided into four groups (n = 8), according to the surface sealant used, including the control, which had no sealant application. Baseline color was measured according to the CIELab system using a reflection spectrophotometer. Surface roughness was determined using a profilometer with a cut-off of 0.25 mm. After these tests, specimens were aged for 252 h in an ultraviolet (UV)-accelerated aging chamber. Color stability was determined by difference between coordinates obtained before and after the aging procedure. Data of color change and roughness were evaluated by anova and Fisher's exact test (α = 0.05). The results showed that the unsealed group had the highest color change compared to other groups (P = 0.0289), and there was no significant difference between groups sealed with surface sealant (P > 0.05). The artificial aging caused an increase in roughness values independent of the experimental group studied (P = 0.0015). The sealed composites showed lower color change after UV aging, but all groups showed clinically-acceptable color change, and only liquid polish decreased roughness. © 2016 John Wiley & Sons Australia, Ltd.

  18. Validation of accelerated ageing of Thales rotary Stirling cryocoolers for the estimation of MTTF

    NASA Astrophysics Data System (ADS)

    Seguineau, C.,; Cauquil, J.-M.; Martin, J.-Y.; Benschop, T.

    2016-05-01

    The cooled IR detectors are used in a wide range of applications. Most of the time, the cryocoolers are one of the components dimensioning the lifetime of the system. The current market needs tend to reliability figures higher than 15,000hrs in "standard conditions". Field returns are hardly useable mostly because of the uncertain environmental conditions of use, or the differences in user profiles. A previous paper explains how Thales Cryogenics has developed an approach based on accelerated ageing and statistical analysis [1]. The aim of the current paper is to compare results obtained on accelerated ageing on one side, and on the other side, specific field returns where the conditions of use are well known. The comparison between prediction and effective failure rate is discussed. Moreover, a specific focus is done on how some new applications of cryocoolers (continuous operation at a specific temperature) can increase the MTTF. Some assumptions are also exposed on how the failure modes, effects and criticality analysis evolves for continuous operation at a specific temperature and compared to experimental data.

  19. Aging and autism spectrum disorder: Evidence from the broad autism phenotype.

    PubMed

    Wallace, Gregory L; Budgett, Jessica; Charlton, Rebecca A

    2016-12-01

    This study investigated for the first time the broad autism phenotype (BAP) in the context of older adulthood and its associations with real-world executive function, social support, and both depression and anxiety symptomatology. Based on self-ratings of autistic traits, 66 older adults (60+ years old, range = 61-88) were split into BAP (n = 20) and control (n = 46) groups. Individuals in the BAP group, even after controlling for age, education level, sex, and health problems, exhibited more real-world executive function problems in multiple domains, reported lower levels of social support, and self-rated increased depression and anxiety symptomatology compared to the control group. Regression analysis revealed that level of social support was the strongest predictor of BAP traits across both groups, although real-world executive function problems and depression symptomatology were also significant predictors. Moreover, when predicting anxiety and depression symptomatology, BAP traits were the strongest predictors above and beyond the effects of demographic factors, real-world executive function problems, and social support levels. These findings suggest that the BAP in older adulthood imparts additional risks to areas of functioning that are known to be crucial to aging-related outcomes in the context of typical development. These results might in turn inform aging in autism spectrum disorder, which has been largely unexplored to date. Autism Res 2016, 9: 1294-1303. © 2016 International Society for Autism Research, Wiley Periodicals, Inc. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

  20. Evolution of the rate of biological aging using a phenotype based computational model.

    PubMed

    Kittas, Aristotelis

    2010-10-07

    In this work I introduce a simple model to study how natural selection acts upon aging, which focuses on the viability of each individual. It is able to reproduce the Gompertz law of mortality and can make predictions about the relation between the level of mutation rates (beneficial/deleterious/neutral), age at reproductive maturity and the degree of biological aging. With no mutations, a population with low age at reproductive maturity R stabilizes at higher density values, while with mutations it reaches its maximum density, because even for large pre-reproductive periods each individual evolves to survive to maturity. Species with very short pre-reproductive periods can only tolerate a small number of detrimental mutations. The probabilities of detrimental (P(d)) or beneficial (P(b)) mutations are demonstrated to greatly affect the process. High absolute values produce peaks in the viability of the population over time. Mutations combined with low selection pressure move the system towards weaker phenotypes. For low values in the ratio P(d)/P(b), the speed at which aging occurs is almost independent of R, while higher values favor significantly species with high R. The value of R is critical to whether the population survives or dies out. The aging rate is controlled by P(d) and P(b) and the amount of the viability of each individual is modified, with neutral mutations allowing the system more "room" to evolve. The process of aging in this simple model is revealed to be fairly complex, yielding a rich variety of results. 2010 Elsevier Ltd. All rights reserved.

  1. Acceleration of leukocytes' epigenetic age as an early tumor and sex-specific marker of breast and colorectal cancer.

    PubMed

    Durso, Danielle Fernandes; Bacalini, Maria Giulia; Sala, Claudia; Pirazzini, Chiara; Marasco, Elena; Bonafé, Massimiliano; do Valle, Ítalo Faria; Gentilini, Davide; Castellani, Gastone; Faria, Ana Maria Caetano; Franceschi, Claudio; Garagnani, Paolo; Nardini, Christine

    2017-04-04

    Changes in blood epigenetic age have been associated with several pathological conditions and have recently been described to anticipate cancer development. In this work, we analyze a publicly available leukocytes methylation dataset to evaluate the relation between DNA methylation age and the prospective development of specific types of cancer. We calculated DNA methylation age acceleration using five state-of-the-art estimators (three multi-site: Horvath, Hannum, Weidner; and two CpG specific: ELOV2 and FHL2) in a cohort including 845 subjects from the EPIC-Italy project and we compared 424 samples that remained cancer-free over the approximately ten years of follow-up with 235 and 166 subjects who developed breast and colorectal cancer, respectively. We show that the epigenetic age estimated from blood DNA methylation data is statistically significantly associated to future breast and male colorectal cancer development. These results are corroborated by survival analysis that shows significant association between age acceleration and cancer incidence suggesting that the chance of developing age-related diseases may be predicted by circulating epigenetic markers, with a dependence upon tumor type, sex and age estimator. These are encouraging results towards the non-invasive and perspective usage of epigenetic biomarkers.

  2. Cross-sectional analysis of the effects of age on the hormonal, metabolic, and ultrasonographic features and the prevalence of the different phenotypes of polycystic ovary syndrome.

    PubMed

    Panidis, Dimitrios; Tziomalos, Konstantinos; Macut, Djuro; Delkos, Dimitrios; Betsas, George; Misichronis, Georgios; Katsikis, Ilias

    2012-02-01

    To assess the effects of age on the hormonal, metabolic, and ultrasonographic features of polycystic ovary syndrome (PCOS). Observational study. University department of obstetrics and gynecology. Patients with PCOS (n = 1,212) and healthy women (n = 254). None. Differences in the hormonal, metabolic, and ultrasonographic features of PCOS between age groups. A progressive decline in circulating androgens was observed with advancing age. Patients 21-30 years old had lower plasma glucose and insulin levels, lower area under the oral glucose tolerance test curve and lower homeostasis model assessment of insulin resistance index, and higher glucose/insulin and quantitative insulin sensitivity check index than patients 31-39 years old. The prevalence of PCOS phenotypes changed with age. More specifically, the distribution of the phenotypes did not differ substantially between patients ≤ 20 years old and patients 21-30 years old. However, a decline in the prevalence of phenotype 1 (characterized by anovulation, hyperandrogenemia, and polycystic ovaries) and an increase in the prevalence of phenotype 4 (characterized by anovulation and polycystic ovaries without hyperandrogenemia) were observed in patients 31-39 years old. In women with PCOS, hyperandrogenemia appears to diminish during reproductive life whereas insulin resistance worsens. Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  3. Accelerated age-related olfactory decline among type 1 Usher patients.

    PubMed

    Ribeiro, João Carlos; Oliveiros, Bárbara; Pereira, Paulo; António, Natália; Hummel, Thomas; Paiva, António; Silva, Eduardo D

    2016-06-22

    Usher Syndrome (USH) is a rare disease with hearing loss, retinitis pigmentosa and, sometimes, vestibular dysfunction. A phenotype heterogeneity is reported. Recent evidence indicates that USH is likely to belong to an emerging class of sensory ciliopathies. Olfaction has recently been implicated in ciliopathies, but the scarce literature about olfaction in USH show conflicting results. We aim to evaluate olfactory impairment as a possible clinical manifestation of USH. Prospective clinical study that included 65 patients with USH and 65 normal age-gender-smoking-habits pair matched subjects. A cross culturally validated version of the Sniffin' Sticks olfaction test was used. Young patients with USH have significantly better olfactory scores than healthy controls. We observe that USH type 1 have a faster ageing olfactory decrease than what happens in healthy subjects, leading to significantly lower olfactory scores in older USH1 patients. Moreover, USH type 1 patients showed significantly higher olfactory scores than USH type 2, what can help distinguishing them. Olfaction represents an attractive tool for USH type classification and pre diagnostic screening due to the low cost and non-invasive nature of the testing. Olfactory dysfunction should be considered among the spectrum of clinical manifestations of Usher syndrome.

  4. Age-related changes in endothelial function and blood flow regulation.

    PubMed

    Toda, Noboru

    2012-02-01

    Vascular endothelial dysfunction is regarded as a primary phenotypic expression of normal human aging. This senescence-induced disorder is the likely culprit underlying the increased cardiovascular and metabolic disease risks associated with aging. The rate of this age-dependent deterioration is largely influenced by the poor-quality lifestyle choice, such as smoking, sedentary daily life, chronic alcohol ingestion, high salt intake, unbalanced diet, and mental stress; and it is accelerated by cardiovascular and metabolic diseases. Although minimizing these detrimental factors is the best course of action, nonetheless chronological age steadily impairs endothelial function through reduced endothelial nitric oxide synthase (eNOS) expression/action, accelerated nitric oxide (NO) degradation, increased phosphodiesterase activity, inhibition of NOS activity by endogenous NOS inhibitors, increased production of reactive oxygen species, inflammatory reactions, decreased endothelial progenitor cell number and function, and impaired telomerase activity or telomere shortening. Endothelial dysfunction in regional vasculatures results in cerebral hypoperfusion triggering cognitive dysfunction and Alzheimer's disease, coronary artery insufficiency, penile erectile dysfunction, and circulatory failures in other organs and tissues. Possible prophylactic measures to minimize age-related endothelial dysfunction are also summarized in this review. Copyright © 2011 Elsevier Inc. All rights reserved.

  5. Soluble immune receptor serum levels are associated with age, but not with clinical phenotype or disease severity in childhood atopic dermatitis.

    PubMed

    Ott, H; Wilke, J; Baron, J M; Höger, P H; Fölster-Holst, R

    2010-04-01

    Soluble immune receptors (SIRs) have been proposed as biomarkers in patients with atopic dermatitis (AD). However, their clinical applicability in affected children has rarely been studied. To assess the diagnostic usefulness of serum SIRs in childhood AD by correlating the obtained receptor profiles with serological parameters and clinical features such as age, AD phenotype and disease severity. We investigated 100 children with AD. The sCD14, sCD23, sCD25, sCD30, total IgE (tIgE) and eosinophilic cationic protein (ECP) were determined using sera of all children. The clinical phenotype was classified as extrinsic AD (ADe) or intrinsic AD (ADi) by the presence of allergen-specific IgE antibodies. A total of 55 male and 45 female children were recruited. The sCD23, sCD25 and sCD30 serum levels revealed significant age-dependency. At a mean SCORAD of 40 (range 8-98), none of the evaluated SIRs was correlated to disease severity. In all, 73% of patients suffered from ADe while 27% showed the ADi phenotype. None of the analysed SIRs differed significantly between ADe and ADi patients, while tIgE and ECP levels were elevated in the ADe subgroup. The current study provides evidence that sCD23, sCD25 and sCD30 serum levels are highly age-dependent. Serum concentrations of all investigated SIRs did not significantly correlate with disease severity in children with AD and were not differentially expressed in patients of different AD phenotypes. Therefore, we believe that the studied SIRs cannot be regarded as clinically useful biomarkers for the assessment of childhood AD.

  6. Primary hypertension is a disease of premature vascular aging associated with neuro-immuno-metabolic abnormalities.

    PubMed

    Litwin, Mieczysław; Feber, Janusz; Niemirska, Anna; Michałkiewicz, Jacek

    2016-02-01

    There is an increasing amount of data indicating that primary hypertension (PH) is not only a hemodynamic phenomenon but also a complex syndrome involving abnormal fat tissue distribution, over-activity of the sympathetic nervous system (SNS), metabolic abnormalities, and activation of the immune system. In children, PH usually presents with a typical phenotype of disturbed body composition, accelerated biological maturity, and subtle immunological and metabolic abnormalities. This stage of the disease is potentially reversible. However, long-lasting over-activity of the SNS and immuno-metabolic alterations usually lead to an irreversible stage of cardiovascular disease. We describe an intermediate phenotype of children with PH, showing that PH is associated with accelerated development, i.e., early premature aging of the immune, metabolic, and vascular systems. The associations and determinants of hypertensive organ damage, the principles of treatment, and the possibility of rejuvenation of the cardiovascular system are discussed.

  7. ACCELERATED FAILURE TIME MODELS PROVIDE A USEFUL STATISTICAL FRAMEWORK FOR AGING RESEARCH

    PubMed Central

    Swindell, William R.

    2009-01-01

    Survivorship experiments play a central role in aging research and are performed to evaluate whether interventions alter the rate of aging and increase lifespan. The accelerated failure time (AFT) model is seldom used to analyze survivorship data, but offers a potentially useful statistical approach that is based upon the survival curve rather than the hazard function. In this study, AFT models were used to analyze data from 16 survivorship experiments that evaluated the effects of one or more genetic manipulations on mouse lifespan. Most genetic manipulations were found to have a multiplicative effect on survivorship that is independent of age and well-characterized by the AFT model “deceleration factor”. AFT model deceleration factors also provided a more intuitive measure of treatment effect than the hazard ratio, and were robust to departures from modeling assumptions. Age-dependent treatment effects, when present, were investigated using quantile regression modeling. These results provide an informative and quantitative summary of survivorship data associated with currently known long-lived mouse models. In addition, from the standpoint of aging research, these statistical approaches have appealing properties and provide valuable tools for the analysis of survivorship data. PMID:19007875

  8. Accelerated failure time models provide a useful statistical framework for aging research.

    PubMed

    Swindell, William R

    2009-03-01

    Survivorship experiments play a central role in aging research and are performed to evaluate whether interventions alter the rate of aging and increase lifespan. The accelerated failure time (AFT) model is seldom used to analyze survivorship data, but offers a potentially useful statistical approach that is based upon the survival curve rather than the hazard function. In this study, AFT models were used to analyze data from 16 survivorship experiments that evaluated the effects of one or more genetic manipulations on mouse lifespan. Most genetic manipulations were found to have a multiplicative effect on survivorship that is independent of age and well-characterized by the AFT model "deceleration factor". AFT model deceleration factors also provided a more intuitive measure of treatment effect than the hazard ratio, and were robust to departures from modeling assumptions. Age-dependent treatment effects, when present, were investigated using quantile regression modeling. These results provide an informative and quantitative summary of survivorship data associated with currently known long-lived mouse models. In addition, from the standpoint of aging research, these statistical approaches have appealing properties and provide valuable tools for the analysis of survivorship data.

  9. Visual evaluation of color stability after accelerated aging of pigmented and nonpigmented silicones to be used in facial prostheses.

    PubMed

    Mancuso, Daniela Nardi; Goiato, Marcelo Coelho; Dekon, Stefan Fiuza de Carvalho; Gennari-Filho, Humberto

    2009-01-01

    The objective of this study was to evaluate by a visual method of comparison the color stability of nonpigmented and pigmented facial silicones after accelerated aging. Two kinds of silicones were used in this study; one specifically formulated for facial prostheses and the other an acetic silicone for industrial use. Twenty-four trial bodies were made for each silicone. These were divided into colorless and intrinsically pigmented groups: ceramic, make-up, and iron oxide. The groups were submitted to accelerated aging for nonmetallic materials. An initial reading and subsequent readings were made at 163, 351, 692, and 1000 hours using a visual method of comparison. The values were annotated in a spreadsheet by two observers, according to scores elaborated for this study. All groups presented color stability in the visual method. According to the results obtained and analyzed in this study, we can conclude that both silicones, Silastic 732 RTV and Silastic MDX 4-4210, behaved similarly, they can therefore be indicated for use in maxillofacial prosthesis. The time factor of aging influenced negatively, independently of the pigmentation, or lack of it, and of silicones and no group had visually noticeable alterations in any of the accelerated aging time, independently of the addition or not of pigments.

  10. White Matter Lesions: Prevalence and Clinical Phenotype in Asymptomatic Individuals Aged ≥50 Years.

    PubMed

    David, Jean-Philippe; Ferrat, Emilie; Parisot, Juliette; Naga, Henri; Lakroun, Samia; Menasria, Feriel; Saddedine, Sofiane; Natella, Pierre-André; Paillaud, Elena; Fromentin, Isabelle; Bastuji-Garin, Sylvie

    2016-01-01

    To assess the prevalence of early confluent/confluent white matter lesions (ec/cWMLs) in asymptomatic individuals aged ≥50 years and to identify associated clinical phenotypes. Cross-sectional analysis of 141 asymptomatic individuals aged ≥50 years assessed at an outpatient department in France. Brain magnetic resonance imaging was rated using the Fazekas scale. Age-adjusted odds ratios (ORs) and 95% confidence intervals were estimated using logistic models to investigate factors associated with ec/cWMLs; independent risk factors were identified by multivariate analysis. Median age was 63 years; 53.9% were women, 32.6% had hypertension, and 76.6% had ≥1 cardiovascular risk factors. The prevalence of ec/cWMLs was 26.2%. Apart from age, independent risk factors were family history of cardiovascular event (OR = 5.55; 1.13-27.32) and hypertension (2.47; 1.05-5.81). Patients with ec/cWMLs had lower cognitive dual-task walking speed (1.15; 0.98-1.40), MMSE (1.41; 1.06-1.89), and FAB scores (5.21; 1.49-19.84). The Scheltens score was independently associated with the WML severity score. ec/cWMLs are common in asymptomatic community-dwelling individuals aged ≥50 years. They are associated with cardiovascular risk factors, impairments in global and executive cognitive function, and Scheltens score elevation. © 2016 S. Karger AG, Basel.

  11. Volatile profile of Madeira wines submitted to traditional accelerated ageing.

    PubMed

    Pereira, Vanda; Cacho, Juan; Marques, José C

    2014-11-01

    The evolution of monovarietal fortified Madeira wines forced-aged by traditional thermal processing (estufagem) were studied in terms of volatiles. SPE extracts were analysed by GC-MS before and after heating at 45 °C for 3 months (standard) and at 70 °C for 1 month (overheating). One hundred and ninety volatile compounds were identified, 53 of which were only encountered in baked wines. Most chemical families increased after standard heating, especially furans and esters, up to 61 and 3-fold, respectively. On the contrary, alcohols, acetates and fatty acids decreased after heating. Varietal aromas, such as Malvasia's monoterpenic alcohols were not detected after baking. The accelerated ageing favoured the development of some volatiles previously reported as typical aromas of finest Madeira wines, particularly phenylacetaldeyde, β-damascenone and 5-ethoxymethylfurfural. Additionally, ethyl butyrate, ethyl 2-methylbutyrate, ethyl caproate, ethyl isovalerate, guaiacol, 5-hydroxymethylfurfural and γ-decalactone were also found as potential contributors to the global aroma of baked wines. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Influence of artificial accelerated aging on dimensional stability of acrylic resins submitted to different storage protocols.

    PubMed

    Garcia, Lucas da Fonseca Roberti; Roselino, Lourenço de Moraes Rego; Mundim, Fabrício Mariano; Pires-de-Souza, Fernanda de Carvalho Panzeri; Consani, Simonides

    2010-08-01

    The aim of this study was to evaluate the influence of artificial accelerated aging on dimensional stability of two types of acrylic resins (thermally and chemically activated) submitted to different protocols of storage. One hundred specimens were made using a Teflon matrix (1.5 cm x 0.5 mm) with four imprint marks, following the lost-wax casting method. The specimens were divided into ten groups, according to the type of acrylic resin, aging procedure, and storage protocol (30 days). GI: acrylic resins thermally activated, aging, storage in artificial saliva for 16 hours, distilled water for 8 hours; GII: thermal, aging, artificial saliva for 16 hours, dry for 8 hours; GIII: thermal, no aging, artificial saliva for 16 hours, distilled water for 8 hours, GIV: thermal, no aging, artificial saliva for 16 hours, dry for 8 hours; GV: acrylic resins chemically activated, aging, artificial saliva for 16 hours, distilled water for 8 hours; GVI: chemical, aging, artificial saliva for 16 hours, dry for 8 hours; GVII: chemical, no aging, artificial saliva for 16 hours, distilled water for 8 hours; GVIII: chemical, no aging, artificial saliva for 16 hours, dry for 8 hours GIX: thermal, dry for 24 hours; and GX: chemical, dry for 24 hours. All specimens were photographed before and after treatment, and the images were evaluated by software (UTHSCSA - Image Tool) that made distance measurements between the marks in the specimens (mm), calculating the dimensional stability. Data were submitted to statistical analysis (two-way ANOVA, Tukey test, p= 0.05). Statistical analysis showed that the specimens submitted to storage in water presented the largest distance between both axes (major and minor), statistically different (p < 0.05) from control groups. All acrylic resins presented dimensional changes, and the artificial accelerated aging and storage period influenced these alterations.

  13. Nonlinear ghost waves accelerate the progression of high-grade brain tumors

    NASA Astrophysics Data System (ADS)

    Pardo, Rosa; Martínez-González, Alicia; Pérez-García, Víctor M.

    2016-10-01

    We study a reduced continuous model describing the evolution of high grade gliomas in response to hypoxic events through the interplay of different cellular phenotypes. We show that hypoxic events, even when sporadic and/or limited in space, may have a crucial role on the acceleration of high grade gliomas growth. Our modeling approach is based on two cellular phenotypes. One of them is more migratory and a second one is more proliferative. Transitions between both phenotypes are driven by the local oxygen values, assumed in this simple model to be uniform. Surprisingly, even very localized in time hypoxia events leading to transient migratory populations have the potential to accelerate the tumor's invasion speed up to speeds close to those of the migratory phenotype. The high invasion speed persists for times much longer than the lifetime of the hypoxic event. Moreover, the phenomenon is observed both when the migratory cells form a persistent wave of cells located on the invasion front and when they form a evanescent "ghost" wave disappearing after a short time by decay to the more proliferative phenotype. Our findings are obtained through numerical simulations of the model equations both in 1D and higher dimensional scenarios. We also provide a deeper mathematical analysis of some aspects of the problem such as the conditions for the existence of persistent waves of cells with a more migratory phenotype.

  14. Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice.

    PubMed

    Vermeij, W P; Dollé, M E T; Reiling, E; Jaarsma, D; Payan-Gomez, C; Bombardieri, C R; Wu, H; Roks, A J M; Botter, S M; van der Eerden, B C; Youssef, S A; Kuiper, R V; Nagarajah, B; van Oostrom, C T; Brandt, R M C; Barnhoorn, S; Imholz, S; Pennings, J L A; de Bruin, A; Gyenis, Á; Pothof, J; Vijg, J; van Steeg, H; Hoeijmakers, J H J

    2016-09-15

    Mice deficient in the DNA excision-repair gene Ercc1 (Ercc1 ∆/- ) show numerous accelerated ageing features that limit their lifespan to 4-6 months. They also exhibit a 'survival response', which suppresses growth and enhances cellular maintenance. Such a response resembles the anti-ageing response induced by dietary restriction (also known as caloric restriction). Here we report that a dietary restriction of 30% tripled the median and maximal remaining lifespans of these progeroid mice, strongly retarding numerous aspects of accelerated ageing. Mice undergoing dietary restriction retained 50% more neurons and maintained full motor function far beyond the lifespan of mice fed ad libitum. Other DNA-repair-deficient, progeroid Xpg -/- (also known as Ercc5 -/- ) mice, a model of Cockayne syndrome, responded similarly. The dietary restriction response in Ercc1 ∆/- mice closely resembled the effects of dietary restriction in wild-type animals. Notably, liver tissue from Ercc1 ∆/- mice fed ad libitum showed preferential extinction of the expression of long genes, a phenomenon we also observed in several tissues ageing normally. This is consistent with the accumulation of stochastic, transcription-blocking lesions that affect long genes more than short ones. Dietary restriction largely prevented this declining transcriptional output and reduced the number of γH2AX DNA damage foci, indicating that dietary restriction preserves genome function by alleviating DNA damage. Our findings establish the Ercc1 ∆/- mouse as a powerful model organism for health-sustaining interventions, reveal potential for reducing endogenous DNA damage, facilitate a better understanding of the molecular mechanism of dietary restriction and suggest a role for counterintuitive dietary-restriction-like therapy for human progeroid genome instability syndromes and possibly neurodegeneration in general.

  15. Colour stability of denture teeth submitted to different cleaning protocols and accelerated artificial aging.

    PubMed

    Freire, T S; Aguilar, F G; Garcia, L da Fonseca Roberti; Pires-de-Souza, F de Carvalho Panzeri

    2014-03-01

    Acrylic resin is widely used for artificial teeth manufacturing due to several important characteristics; however, this material do not present acceptable colour stability over the course of time. This study evaluated the effect of different cleaning protocols and accelerated artificial aging on colour stability of denture teeth made of acrylic resin. Sixty denture teeth in dark and light shades were used, and separated according to the treatment to which they were submitted. Results demonstrated that colour stability of artificial teeth is influenced by the cleaning solution and artificial aging, being dark teeth more susceptible to colour alteration than lighter ones.

  16. A Model-based Prognostics Methodology for Electrolytic Capacitors Based on Electrical Overstress Accelerated Aging

    NASA Technical Reports Server (NTRS)

    Celaya, Jose; Kulkarni, Chetan; Biswas, Gautam; Saha, Sankalita; Goebel, Kai

    2011-01-01

    A remaining useful life prediction methodology for electrolytic capacitors is presented. This methodology is based on the Kalman filter framework and an empirical degradation model. Electrolytic capacitors are used in several applications ranging from power supplies on critical avionics equipment to power drivers for electro-mechanical actuators. These devices are known for their comparatively low reliability and given their criticality in electronics subsystems they are a good candidate for component level prognostics and health management. Prognostics provides a way to assess remaining useful life of a capacitor based on its current state of health and its anticipated future usage and operational conditions. We present here also, experimental results of an accelerated aging test under electrical stresses. The data obtained in this test form the basis for a remaining life prediction algorithm where a model of the degradation process is suggested. This preliminary remaining life prediction algorithm serves as a demonstration of how prognostics methodologies could be used for electrolytic capacitors. In addition, the use degradation progression data from accelerated aging, provides an avenue for validation of applications of the Kalman filter based prognostics methods typically used for remaining useful life predictions in other applications.

  17. Nuclear DNA Methylation and Chromatin Condensation Phenotypes Are Distinct Between Normally Proliferating/Aging, Rapidly Growing/Immortal, and Senescent Cells

    PubMed Central

    Gertych, Arkadiusz; Tajbakhsh, Jian

    2013-01-01

    This study reports on probing the utility of in situ chromatin texture features such as nuclear DNA methylation and chromatin condensation patterns — visualized by fluorescent staining and evaluated by dedicated three-dimensional (3D) quantitative and high-throughput cell-by-cell image analysis — in assessing the proliferative capacity, i.e. growth behavior of cells: to provide a more dynamic picture of a cell population with potential implications in basic science, cancer diagnostics/prognostics and therapeutic drug development. Two types of primary cells and four different cancer cell lines were propagated and subjected to cell-counting, flow cytometry, confocal imaging, and 3D image analysis at various points in culture. Additionally a subset of primary and cancer cells was accelerated into senescence by oxidative stress. DNA methylation and chromatin condensation levels decreased with declining doubling times when primary cells aged in culture with the lowest levels reached at the stage of proliferative senescence. In comparison, immortal cancer cells with constant but higher doubling times mostly displayed lower and constant levels of the two in situ-derived features. However, stress-induced senescent primary and cancer cells showed similar levels of these features compared with primary cells that had reached natural growth arrest. With regards to global DNA methylation and chromatin condensation levels, aggressively growing cancer cells seem to take an intermediate level between normally proliferating and senescent cells. Thus, normal cells apparently reach cancer-cell equivalent stages of the two parameters at some point in aging, which might challenge phenotypic distinction between these two types of cells. Companion high-resolution molecular profiling could provide information on possible underlying differences that would explain benign versus malign cell growth behaviors. PMID:23562889

  18. Phenotypic plasticity in age at first reproduction of female northern sea otters (Enhydra lutris kenyoni)

    USGS Publications Warehouse

    Von Biela, V.R.; Gill, V.A.; Bodkin, James L.; Burns, Jennifer M.

    2009-01-01

    Life-history theory predicts that within a species, reproduction and survival rates will differ among populations that differ in resource availability or predation rates through phenotypic plasticity. When populations are near carrying capacity (K) or when they are declining due to reduced prey resources, the average age at 1st reproduction (average AFR) is predicted to be older than in populations below K. Differences between the trajectories of northern sea otter (Enhydra lutris kenyoni) populations in Alaska provides an opportunity to examine phenotypic plasticity. Using premolar teeth or reproductive tracts, we estimated average AFR from demographically distinct populations of sea otters in Alaska. We obtained samples from 2 populations near K, Prince William Sound (PWS) and the Aleutian Archipelago (archived samples), and from 2populations below K, the Kodiak Archipelago and Sitka. The average AFR was lower in populations below K (3.60 years ??0.16 SD)compared to those near K (4.21 ?? 0.13 years, P <0.001), and differed among all populations, with the Aleutian population possessing the oldest average AFR (4.29 ?? 0.09 years) followed by PWS (4.05 ?? 0.24 years), Sitka (3.80 ?? 0.21 years), and Kodiak (3.19 ?? 0.37 years). The difference in average AFR among populations supports life-history theory and provides evidence of phenotypic plasticity in sea otters. Our findings highlight the value of using average AFR as a tool for monitoring mammalian populations. ?? 2009 American Society of Mammalogists.

  19. Shear banding leads to accelerated aging dynamics in a metallic glass

    NASA Astrophysics Data System (ADS)

    Küchemann, Stefan; Liu, Chaoyang; Dufresne, Eric M.; Shin, Jeremy; Maaß, Robert

    2018-01-01

    Traditionally, strain localization in metallic glasses is related to the thickness of the shear defect, which is confined to the nanometer scale. Using site-specific x-ray photon correlation spectroscopy, we reveal significantly accelerated relaxation dynamics around a shear band in a metallic glass at a length scale that is orders of magnitude larger than the defect itself. The relaxation time in the shear-band vicinity is up to ten times smaller compared to the as-cast matrix, and the relaxation dynamics occurs in a characteristic three-stage aging response that manifests itself in the temperature-dependent shape parameter known from classical stretched exponential relaxation dynamics of disordered materials. We demonstrate that the time-dependent correlation functions describing the aging at different temperatures can be captured and collapsed using simple scaling functions. These insights highlight how a ubiquitous nanoscale strain-localization mechanism in metallic glasses leads to a fundamental change of the relaxation dynamics at the mesoscale.

  20. Accelerated age-related olfactory decline among type 1 Usher patients

    PubMed Central

    Ribeiro, João Carlos; Oliveiros, Bárbara; Pereira, Paulo; António, Natália; Hummel, Thomas; Paiva, António; Silva, Eduardo D.

    2016-01-01

    Usher Syndrome (USH) is a rare disease with hearing loss, retinitis pigmentosa and, sometimes, vestibular dysfunction. A phenotype heterogeneity is reported. Recent evidence indicates that USH is likely to belong to an emerging class of sensory ciliopathies. Olfaction has recently been implicated in ciliopathies, but the scarce literature about olfaction in USH show conflicting results. We aim to evaluate olfactory impairment as a possible clinical manifestation of USH. Prospective clinical study that included 65 patients with USH and 65 normal age-gender-smoking-habits pair matched subjects. A cross culturally validated version of the Sniffin’ Sticks olfaction test was used. Young patients with USH have significantly better olfactory scores than healthy controls. We observe that USH type 1 have a faster ageing olfactory decrease than what happens in healthy subjects, leading to significantly lower olfactory scores in older USH1 patients. Moreover, USH type 1 patients showed significantly higher olfactory scores than USH type 2, what can help distinguishing them. Olfaction represents an attractive tool for USH type classification and pre diagnostic screening due to the low cost and non-invasive nature of the testing. Olfactory dysfunction should be considered among the spectrum of clinical manifestations of Usher syndrome. PMID:27329700

  1. AGE IS RELEVANT: DISTINCTIVE RISK FACTORS AND PHENOTYPE OF YOUNGER PATIENTS WITH RESISTANT HYPERTENSION

    PubMed Central

    Ghazi, Lama; Oparil, Suzanne; Calhoun, David A.; Lin, Chee Paul; Dudenbostel, Tanja

    2017-01-01

    Resistant hypertension, defined as blood pressure >140/90 mmHg despite using ≥3 antihypertensive medications, is a well-recognized clinical entity. Patients with resistant hypertension are at an increased risk of cardiovascular disease compared with those with more easily controlled hypertension. Coronary heart disease mortality rates of younger adults are stagnating or on the rise. The purpose of our study was to characterize the phenotype and risk factors of younger patients with resistant hypertension given the dearth of data on cardiovascular risk profile in this cohort. We conducted a cross sectional analysis with predefined age groups of a large, ethnically diverse cohort of 2170 patients referred to the Hypertension Clinic at the University of Alabama at Birmingham. 2068 patients met the inclusion criteria and were classified by age groups, i.e. ≤40 yrs (12.7 % of total cohort), 41–55 yrs (32.1%), 56–70 yrs (36.1%) and ≥71 yrs (19.1%). Patients ≤40 yrs of age compared with ≥71 yrs, had significantly earlier onset of HTN (24.7±7.4vs 55.0±14.1 yrs, p<0.0001), higher rates of obesity (53.4% vs 26.9%, p<0.0001), and significantly higher levels of plasma aldosterone (11.3±9.8 vs 8.9±7.4 ng/dl, p=0.005), plasma renin activity (4.9±10.2 vs 2.5±5.0 ng/ml/hr, p=0.001), and 24-hr urinary aldosterone (13.4±10.0 vs 8.2±6.2 μg/24hr, p<0.0001) and sodium excretion (195.9±92.0 vs 146.8±67.1 mEq/24hr, p<0.0001). Among patients with resistant hypertension, younger individuals have a distinct phenotype characterized by overlapping risk factors and comorbidities, including obesity, high aldosterone and high dietary sodium intake compared to elderly. PMID:28348010

  2. Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice

    PubMed Central

    Safdar, Adeel; Bourgeois, Jacqueline M.; Ogborn, Daniel I.; Little, Jonathan P.; Hettinga, Bart P.; Akhtar, Mahmood; Thompson, James E.; Melov, Simon; Mocellin, Nicholas J.; Kujoth, Gregory C.; Prolla, Tomas A.; Tarnopolsky, Mark A.

    2011-01-01

    A causal role for mitochondrial DNA (mtDNA) mutagenesis in mammalian aging is supported by recent studies demonstrating that the mtDNA mutator mouse, harboring a defect in the proofreading-exonuclease activity of mitochondrial polymerase gamma, exhibits accelerated aging phenotypes characteristic of human aging, systemic mitochondrial dysfunction, multisystem pathology, and reduced lifespan. Epidemiologic studies in humans have demonstrated that endurance training reduces the risk of chronic diseases and extends life expectancy. Whether endurance exercise can attenuate the cumulative systemic decline observed in aging remains elusive. Here we show that 5 mo of endurance exercise induced systemic mitochondrial biogenesis, prevented mtDNA depletion and mutations, increased mitochondrial oxidative capacity and respiratory chain assembly, restored mitochondrial morphology, and blunted pathological levels of apoptosis in multiple tissues of mtDNA mutator mice. These adaptations conferred complete phenotypic protection, reduced multisystem pathology, and prevented premature mortality in these mice. The systemic mitochondrial rejuvenation through endurance exercise promises to be an effective therapeutic approach to mitigating mitochondrial dysfunction in aging and related comorbidities. PMID:21368114

  3. Transgenic mice overexpressing glia maturation factor-β, an oxidative stress inducible gene, show premature aging due to Zmpste24 down-regulation.

    PubMed

    Imai, Rika; Asai, Kanae; Hanai, Jun-ichi; Takenaka, Masaru

    2015-07-01

    Glia Maturation Factor-β (GMF), a brain specific protein, is induced by proteinuria in renal tubules. Ectopic GMF overexpression causes apoptosisin vitro via cellular vulnerability to oxidative stress. In order to examine the roles of GMF in non-brain tissue, we constructed transgenic mice overexpressing GMF (GMF-TG). The GMF-TG mice exhibited appearance phenotypes associated with premature aging. The GMF-TG mice also demonstrated short lifespans and reduced hair regrowth, suggesting an accelerated aging process. The production of an abnormal lamin A, a nuclear envelope protein, plays a causal role in both normal aging and accelerated aging diseases, known as laminopathies. Importantly, we identified the abnormal lamin A (prelamin A), accompanied by a down-regulation of a lamin A processing enzyme (Zmpste24) in the kidney of the GMF-TG mice. The GMF-TG mice showed accelerated aging in the kidney, compared with wild-type mice, showing increased TGF-β1, CTGF gene and serum creatinine. The gene expression of p21/waf1 was increased at an earlier stage of life, at 10 weeks, which was in turn down-regulated at a later stage, at 60 weeks. In conclusion, we propose that GMF-TG mice might be a novel mouse model of accelerated aging, due to the abnormal lamin A.

  4. Effects of different surface treatments and accelerated artificial aging on the bond strength of composite resin repairs.

    PubMed

    Melo, Marco Aurélio Veiga de; Moysés, Marcos Ribeiro; Santos, Saulo Galvão dos; Alcântara, Carlos Eduardo Pinto; Ribeiro, José Carlos Rabelo

    2011-01-01

    The purpose of the present study was to assess the bond strength of composite resin repairs subjected to different surface treatments and accelerated artificial aging. 192 cylindrical samples (CSs) were prepared and divided into 24 groups (n = 8). Half of the CSs were stored in water for 24 h, and the other half were subjected to C-UV accelerated aging for non-metallic specimens. The treatments were phosphoric acid + silane + adhesive (PSA); phosphoric acid + adhesive (PA); diamond bur + phosphoric acid + silane + adhesive (DPSA); diamond bur + phosphoric acid + adhesive (DPA); air abrasion + phosphoric acid + silane + adhesive (APSA); and air abrasion + phosphoric acid + adhesive (APA). The repair was performed and the specimens were again aged as described above. A control group (n = 8) was established and did not receive any type of aging or surface treatment. The specimens were loaded to failure in shear mode with a crosshead speed of 0.5 mm/min until fracture. Data were analyzed by one-way ANOVA/Tukey's test (p < 0.05). No statistically significant differences were found among DPSA, DPA, APSA, APA, and the control group. The aged PSA and PA achieved low bonding values and were statistically different from the control group, whereas the non-aged PSA and PA presented no statistically significant difference from the control group. Repairs with the proposed surface treatments were viable on both recent and aged restorations; however, phosphoric acid + adhesive alone were effective only on recent restorations.

  5. Gradual Phenotype Development in Huntington Disease Transgenic Minipig Model at 24 Months of Age.

    PubMed

    Vidinská, Daniela; Vochozková, Petra; Šmatlíková, Petra; Ardan, Taras; Klíma, Jiří; Juhás, Štefan; Juhásová, Jana; Bohuslavová, Božena; Baxa, Monika; Valeková, Ivona; Motlík, Jan; Ellederová, Zdenka

    2018-06-05

    Huntington disease (HD) is an incurable neurodegenerative disease caused by the expansion of a polyglutamine sequence in a gene encoding the huntingtin (Htt) protein, which is expressed in almost all cells of the body. In addition to small animal models, new therapeutic approaches (including gene therapy) require large animal models as their large brains are a more realistic model for translational research. In this study, we describe phenotype development in transgenic minipigs (TgHD) expressing the N-terminal part of mutated human Htt at the age of 24 months. TgHD and wild-type littermates were compared. Western blot analysis and subcellular fractionation of different tissues was used to determine the fragmentation of Htt. Immunohistochemistry and optical analysis of coronal sections measuring aggregates, Htt expression, neuroinflammation, and myelination was applied. Furthermore, the expression of Golgi protein acyl-CoA binding domain containing 3 (ACBD3) was analyzed. We found age-correlated Htt fragmentation in the brain. Among various tissues studied, the testes displayed the highest fragmentation, with Htt fragments detectable even in cell nuclei. Also, Golgi protein ACBD3 was upregulated in testes, which is in agreement with previously reported testicular degeneration in TgHD minipigs. Nevertheless, the TgHD-specific mutated Htt fragments were also present in the cytoplasm of striatum and cortex cells. Moreover, microglial cells were activated and myelination was slightly decreased, suggesting the development of a premanifest stage of neurodegeneration in TgHD minipigs. The gradual development of a neurodegenerative phenotype, ac-companied with testicular degeneration, is observed in 24- month-old TgHD minipigs. © 2018 S. Karger AG, Basel.

  6. Colour stability and opacity of resin cements and flowable composites for ceramic veneer luting after accelerated ageing.

    PubMed

    Archegas, Lucí Regina Panka; Freire, Andrea; Vieira, Sergio; Caldas, Danilo Biazzetto de Menezes; Souza, Evelise Machado

    2011-11-01

    Colour changes of the luting material can become clinically visible affecting the aesthetic appearance of thin ceramic laminates. The aim of this in vitro study was to evaluate the colour stability and opacity of light- and dual-cured resin cements and flowable composites after accelerated ageing. The luting agents were bonded (0.2 mm thick) to ceramic disks (0.75 mm thick) built with the pressed-ceramic IPS Aesthetic Empress (n=7). Colour measurements were determined using a FTIR spectrophotometer before and after accelerated ageing in a weathering machine with a total energy of 150 kJ. Changes in colour (ΔE) and opacity (ΔO) were obtained using the CIE L*a*b* system. The results were submitted to one-way ANOVA, Tukey HSD test and Student's t test (α=5%). All the materials showed significant changes in colour and opacity. The ΔE of the materials ranged from 0.41 to 2.40. The highest colour changes were attributed to RelyX ARC and AllCem, whilst lower changes were found in Variolink Veneer, Tetric Flow and Filtek Z350 Flow. The opacity of the materials ranged from -0.01 to 1.16 and its variation was not significant only for Opallis Flow and RelyX ARC. The accelerated ageing led to colour changes in all the evaluated materials, although they were considered clinically acceptable (ΔE<3). Amongst the dual-cured resin cements, Variolink II demonstrated the highest colour stability. All the flowable composites showed proper colour stability for the luting of ceramic veneers. After ageing, an increase in opacity was observed for most of the materials. Copyright © 2011 Elsevier Ltd. All rights reserved.

  7. Genome-Wide Identification of Regulatory Sequences Undergoing Accelerated Evolution in the Human Genome

    PubMed Central

    Dong, Xinran; Wang, Xiao; Zhang, Feng; Tian, Weidong

    2016-01-01

    Accelerated evolution of regulatory sequence can alter the expression pattern of target genes, and cause phenotypic changes. In this study, we used DNase I hypersensitive sites (DHSs) to annotate putative regulatory sequences in the human genome, and conducted a genome-wide analysis of the effects of accelerated evolution on regulatory sequences. Working under the assumption that local ancient repeat elements of DHSs are under neutral evolution, we discovered that ∼0.44% of DHSs are under accelerated evolution (ace-DHSs). We found that ace-DHSs tend to be more active than background DHSs, and are strongly associated with epigenetic marks of active transcription. The target genes of ace-DHSs are significantly enriched in neuron-related functions, and their expression levels are positively selected in the human brain. Thus, these lines of evidences strongly suggest that accelerated evolution on regulatory sequences plays important role in the evolution of human-specific phenotypes. PMID:27401230

  8. Enhanced Molecular Aging in Late-Life Depression: the Senescent-Associated Secretory Phenotype.

    PubMed

    Diniz, Breno Satler; Reynolds, Charles F; Sibille, Etienne; Lin, Chien-Wei; Tseng, George; Lotrich, Francis; Aizenstein, Howard J; Butters, Meryl A

    2017-01-01

    This study aims to investigate whether a systemic molecular pattern associated with aging (senescent-associated secretory phenotype [SASP]) is elevated in adults with late-life depression (LLD), compared with never-depressed elderly comparison participants. Cross-sectional study. We included 111 older adults (80 with LLD and 31 comparison participants) in this study. A panel of 22 SASP-related proteins was extracted from a previous multiplex protein panel performed in these participants. We conducted a principal component analysis to create the SASP index based on individual weights of each of protein. Participants with LLD showed a significantly increased SASP index compared with comparison participants, after controlling for age, depressive symptoms, medical comorbidity (CIRS-G) scores, sex, and cognitive performance (F (1,98)  = 7.3, p = 0.008). Correlation analyses revealed that the SASP index was positively correlated with age (r = 0.2, p = 0.03) and CIRS score (r = 0.27, p = 0.005), and negatively correlated with information processing speed (r = -0.34, p = 0.001), executive function (r = -0.27, p = 0.004) and global cognitive performance (r = -0.28, p = 0.007). To the best of our knowledge, this is the first study to show that a set of proteins (i.e., SASP index) primarily associated with cellular aging is abnormally regulated and elevated in LLD. These results suggest that individuals with LLD display enhanced aging-related molecular patterns that are associated with higher medical comorbidity and worse cognitive function. Finally, we provide a set of proteins that can serve as potential therapeutic targets and biomarkers to monitor the effects of therapeutic or preventative interventions in LLD. Copyright © 2017 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

  9. Enhanced molecular aging in late-life depression: the Senescent Associated Secretory Phenotype

    PubMed Central

    Diniz, Breno Satler; Reynolds, Charles F.; Sibille, Etienne; Lin, Chien-Wei; Tseng, George; Lotrich, Francis; Aizenstein, Howard J.; Butters, Meryl A.

    2016-01-01

    Objective This study aims to investigate whether a systemic molecular pattern associated with aging (senescent-associated secretory phenotype – SASP) is elevated in adults with late-life depression (LLD), compared to never-depressed elderly comparison participants. Design Cross-sectional study. Participants We included 111 older adults (80 with LLD and 31 comparison participants) in this study. Measurement A panel of 22 SASP-related proteins was extracted from a previous multiplex protein panel performed in these participants. We conducted a principal component analysis to create the SASP index based on individual weights of each of protein. Results Participants with LLD showed a significantly increased SASP index compared to comparison participants, after controlling for age, depressive symptoms, medical comorbidity (CIRS-G) scores, gender, and cognitive performance (F(1,98)=7.3, p=0.008). Correlation analyses revealed that the SASP index was positively correlated with age (r=0.2, p = 0.03) and CIRS score (r=0.27, p=0.005), and negatively correlated with information processing speed (r=−0.34, p=0.001), executive function (r=−0.27, p=0.004) and global cognitive performance (r=−0.28, p=0.007). Conclusions To the best of our knowledge, this is the first study to show that a set of proteins (i.e., SASP index) primarily associated with cellular aging, is abnormally regulated and elevated in LLD. These results suggest that individuals with LLD display enhanced aging-related molecular patterns that are associated with higher medical comorbidity and worse cognitive function. Finally, we provide a set of proteins that can serve as potential therapeutic targets and biomarkers to monitor the effects of therapeutic or preventative interventions in LLD. PMID:27856124

  10. Phenotypes Associated with SHOX Deficiency.

    PubMed

    Ross, J L; Scott, C; Marttila, P; Kowal, K; Nass, A; Papenhausen, P; Abboudi, J; Osterman, L; Kushner, H; Carter, P; Ezaki, M; Elder, F; Wei, F; Chen, H; Zinn, A R

    2001-12-01

    Leri-Weill dyschondrosteosis (LWD) (MIM 127300) is a dominantly inherited skeletal dysplasia characterized phenotypically by Madelung wrist deformity, mesomelia, and short stature. LWD can now be defined genetically by haploinsufficiency of the SHOX (short stature homeobox-containing) gene. We have studied 21 LWD families (43 affected LWD subjects, including 32 females and 11 males, ages 3-56 yr) with confirmed SHOX abnormalities. We investigated the relationship between SHOX mutations, height deficit, and Madelung deformity to determine the contribution of SHOX haploinsufficiency to the LWD and Turner syndrome (TS) phenotypes. Also, we examined the effects of age, gender, and female puberty (estrogen) on the LWD phenotype. SHOX deletions were present in affected individuals from 17 families (81%), and point mutations were detected in 4 families (19%). In the LWD subjects, height deficits ranged from -4.6 to +0.6 SD (mean +/- SD = -2.2 +/- 1.0). There were no statistically significant effects of age, gender, pubertal status, or parental origin of SHOX mutations on height z-score. The height deficit in LWD is approximately two thirds that of TS. Madelung deformity was present in 74% of LWD children and adults and was more frequent and severe in females than males. The prevalence of the Madelung deformity was higher in the LWD vs. a TS population. The prevalence of increased carrying angle, high arched palate, and scoliosis was similar in the two populations. In conclusion, SHOX deletions or mutations accounted for all of our LWD cases. SHOX haploinsufficiency accounts for most, but not all, of the TS height deficit. The LWD phenotype shows some gender- and age-related differences.

  11. Age-Related Changes in Bone Morphology Are Accelerated in Group VIA Phospholipase A2 (iPLA2β)-Null Mice

    PubMed Central

    Ramanadham, Sasanka; Yarasheski, Kevin E.; Silva, Matthew J.; Wohltmann, Mary; Novack, Deborah Veis; Christiansen, Blaine; Tu, Xiaolin; Zhang, Sheng; Lei, Xiaoyong; Turk, John

    2008-01-01

    Phospholipases A2 (PLA2) hydrolyze the sn−2 fatty acid substituent, such as arachidonic acid, from phospholipids, and arachidonate metabolites are recognized mediators of bone modeling. We have previously generated knockout (KO) mice lacking the group VIA PLA2 (iPLA2β), which participates in a variety of signaling events; iPLA2β mRNA is expressed in bones of wild-type (WT) but not KO mice. Cortical bone size, trabecular bone volume, bone mineralizing surfaces, and bone strength are similar in WT and KO mice at 3 months and decline with age in both groups, but the decreases are more pronounced in KO mice. The lower bone mass phenotype observed in KO mice is not associated with an increase in osteoclast abundance/activity or a decrease in osteoblast density, but is accompanied by an increase in bone marrow fat. Relative to WT mice, undifferentiated bone marrow stromal cells (BMSCs) from KO mice express higher levels of PPAR-γ and lower levels of Runx2 mRNA, and this correlates with increased adipogenesis and decreased osteogenesis in BMSCs from these mice. In summary, our studies indicate that age-related losses in bone mass and strength are accelerated in iPLA2β-null mice. Because adipocytes and osteoblasts share a common mesenchymal stem cell origin, our findings suggest that absence of iPLA2β causes abnormalities in osteoblast function and BMSC differentiation and identify a previously unrecognized role of iPLA2β in bone formation. PMID:18349124

  12. Auditory Phenotype of Smith-Magenis Syndrome

    ERIC Educational Resources Information Center

    Brendal, Megan A.; King, Kelly A.; Zalewski, Christopher K.; Finucane, Brenda M.; Introne, Wendy; Brewer, Carmen C.; Smith, Ann C. M.

    2017-01-01

    Purpose: The purpose of this study was to describe the auditory phenotype of a large cohort with Smith-Magenis syndrome (SMS), a rare disorder including physical anomalies, cognitive deficits, sleep disturbances, and a distinct behavioral phenotype. Method: Hearing-related data were collected for 133 individuals with SMS aged 1-49 years. Audiogram…

  13. Joint-Attention and the Social Phenotype of School-Aged Children with ASD.

    PubMed

    Mundy, Peter; Novotny, Stephanie; Swain-Lerro, Lindsey; McIntyre, Nancy; Zajic, Matt; Oswald, Tasha

    2017-05-01

    The validity of joint attention assessment in school-aged children with ASD is unclear (Lord, Jones, Journal of Child Psychology and Psychiatry 53(5):490-509, 2012). This study examined the feasibility and validity of a parent-report measure of joint attention related behaviors in verbal children and adolescents with ASD. Fifty-two children with ASD and 34 controls were assessed with the Childhood Joint Attention Rating Scale (C-JARS). The C-JARS exhibited internally consistency, α = 0.88, and one factor explained 49% of the scale variance. Factor scores correctly identified between 88 and 94% of the children with ASD and 62-82% of controls. These scores were correlated with the ADOS-2, but not other parent-report symptom measures. The C-JARS appears to assess a unique dimension of the social-phenotype of children with ASD.

  14. Effect of accelerated environmental aging on tensile properties of oil palm/jute hybrid composites

    NASA Astrophysics Data System (ADS)

    Jawaid, M.; Saba, N.; Alothman, O.; Paridah, M. T.

    2016-11-01

    Recently natural fibre based hybrid composites are receiving growing consideration due to environmental and biodegradability properties. In order to look behaviour of hybrid composites in outdoor applications, its environmental degradation properties such as UV accelerated weathering properties need to analyze. In this study oil palm empty fruit bunch (EFB) and jute fibres reinforced hybrid composites, pure EFB, pure jute and epoxy composites were fabricated through hand lay-up techniques. Hybrid composites with different layering pattern (EFB/jute/EFB and Jute/EFB/jute) while maintaining 40 wt. % total fibre loading were fabricates to compared with EFB and jute composites. Effect of UV accelerated environmental aging on tensile properties of epoxy, pure EFB, pure jute, and hybrid composites were assessed and evaluate under UV exposure. Tensile samples of all composites were subjected to accelerated weathering for 100h, at temperature (75°C), relative humidity (35%), Light (125 W/m2), and water spray off. Obtained results indicated that there is reduction in tensile strength, modulus and elongation at break values of hybrid and pure composites due to degradation of lignin and fibre-matrix interfacial bonding.

  15. Evaluation of effect of laser etching on shear bond strength between maxillofacial silicone and acrylic resin subjected to accelerated aging process.

    PubMed

    Rhea, Antonette; Ahila, S C; Kumar, B Muthu

    2017-01-01

    Maxillofacial prosthesis are supported by implants, require a retentive matrix to retain the suprastructure. The retentive matrix is made up of acrylic resin to which the silicone prostheses are anchored by micro-mechanical bond. The delamination of silicone away from the retentive matrix is a persisting problem in implant-supported maxillofacial prosthesis. This study aimed to evaluate the effect of laser etching on the shear bond strength (BS) between acrylic resin and maxillofacial silicone, after 24 h of fabrication and after 200 h of accelerated aging. The samples were prepared according to ISO/TR 11405:1994 in maxillofacial silicone and polymethyl methacrylate resin. The untreated samples were Group A (control), Group B (silicon carbide [SiC] paper abrasion 80 grit size), and Group C (erbium-doped yttrium aluminum garnet laser etching). Then, the samples were coated with primer and bonded to maxillofacial silicone. The samples were subjected to shear BS test in an universal testing machine after 24 h of fabrication and after 200 h of accelerated aging. The results were statistically analyzed using one-way ANOVA and Tukey's HSD post hoc test. The shear BS test after 24 h of fabrication showed better BS in SiC paper abrasion. The shear BS test after 200 h of accelerated aging showed better BS in laser etching compared to SiC abrasion. Laser etching produced better shear BS compared to conventional SiC paper abrasion after 200 h of accelerated aging process.

  16. Life at the extreme limit: phenotypic characteristics of supercentenarians in Okinawa.

    PubMed

    Willcox, D Craig; Willcox, Bradley J; Wang, Nien-Chiang; He, Qimei; Rosenbaum, Matthew; Suzuki, Makoto

    2008-11-01

    As elite representatives of the rapidly increasing "oldest-old" population, centenarians have become an important model population for understanding human aging. However, as we are beginning to understand more about this important phenotype, another demographic group of even more elite survivors is emerging-so-called "supercentenarians" or those who survive 110-plus years. Little is known about these exceptional survivors. We assessed the Okinawa Centenarian Study (OCS) database for all information on supercentenarians. The database includes dates of birth and year of death for all residents of Okinawa 99 years old or older and a yearly geriatric assessment of all centenarians who consented, enabling prospective study of age-related traits. Of 20 potential supercentenarians identified, 15 had agreed to participate in the OCS interview, physical examination, and blood draw. Of these 15, 12 (3 men and 9 women) met our age validation criteria and were accepted as supercentenarians. Phenotypic variables studied include medical and social history, activities of daily living (ADLs), and clinical phenotypes (physiology, hematology, biochemistry, and immunology). Age at death ranged from 110 to 112 years. The majority of supercentenarians had minimal clinically apparent disease until late in life, with cataracts (42%) and fractures (33%) being common and coronary heart disease (8%), stroke (8%), cancer (0%), and diabetes (0%) rare or not evident on clinical examination. Functionally, most supercentenarians were independent in ADLs at age 100 years, and few were institutionalized before the age of 105 years. Most had normal clinical parameters at age 100 years, but by age 105 exhibited multiple clinical markers of frailty coincident with a rapid ADL decline. Supercentenarians displayed an exceptionally healthy aging phenotype where clinically apparent major chronic diseases and disabilities were markedly delayed, often beyond age 100. They had little clinical history of

  17. Senescent intervertebral disc cells exhibit perturbed matrix homeostasis phenotype.

    PubMed

    Ngo, Kevin; Patil, Prashanti; McGowan, Sara J; Niedernhofer, Laura J; Robbins, Paul D; Kang, James; Sowa, Gwendolyn; Vo, Nam

    2017-09-01

    Aging greatly increases the risk for intervertebral disc degeneration (IDD) as a result of proteoglycan loss due to reduced synthesis and enhanced degradation of the disc matrix proteoglycan (PG). How disc matrix PG homeostasis becomes perturbed with age is not known. The goal of this study is to determine whether cellular senescence is a source of this perturbation. We demonstrated that disc cellular senescence is dramatically increased in the DNA repair-deficient Ercc1 -/Δ mouse model of human progeria. In these accelerated aging mice, increased disc cellular senescence is closely associated with the rapid loss of disc PG. We also directly examine PG homeostasis in oxidative damage-induced senescent human cells using an in vitro cell culture model system. Senescence of human disc cells treated with hydrogen peroxide was confirmed by growth arrest, senescence-associated β-galactosidase activity, γH2AX foci, and acquisition of senescence-associated secretory phenotype. Senescent human disc cells also exhibited perturbed matrix PG homeostasis as evidenced by their decreased capacity to synthesize new matrix PG and enhanced degradation of aggrecan, a major matrix PG. of the disc. Our in vivo and in vitro findings altogether suggest that disc cellular senescence is an important driver of PG matrix homeostatic perturbation and PG loss. Published by Elsevier B.V.

  18. On the Use of Accelerated Aging Methods for Screening High Temperature Polymeric Composite Materials

    NASA Technical Reports Server (NTRS)

    Gates, Thomas S.; Grayson, Michael A.

    1999-01-01

    A rational approach to the problem of accelerated testing of high temperature polymeric composites is discussed. The methods provided are considered tools useful in the screening of new materials systems for long-term application to extreme environments that include elevated temperature, moisture, oxygen, and mechanical load. The need for reproducible mechanisms, indicator properties, and real-time data are outlined as well as the methodologies for specific aging mechanisms.

  19. Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice.

    PubMed

    Huang, Huang; Nie, Sipei; Cao, Min; Marshall, Charles; Gao, Junying; Xiao, Na; Hu, Gang; Xiao, Ming

    2016-08-01

    Transgenic APPSwe/PS1dE9 (APP/PS1) mice that overproduce amyloid beta (Aβ) are extensively used in the studies of pathogenesis and experimental therapeutics and new drug screening for Alzheimer's disease (AD). However, most of the current literature uses young or adult APP/PS1 mice. In order to provide a broader view of AD-like phenotype of this animal model, in this study, we systematically analyzed behavioral and pathological profiles of 24-month-old male APP/PS1 mice. Aged APP/PS1 mice had reference memory deficits as well as anxiety, hyperactivity, and social interaction impairment. Consistently, there was obvious deposition of amyloid plaques in the dorsal hippocampus with decreased expression of insulin-degrading enzyme, a proteolytic enzyme responsible for degradation of intracellular Aβ. Furthermore, decreases in hippocampal volume, neuronal number and synaptophysin expression, and astrocyte atrophy were also observed in aged APP/PS1 mice. This finding suggests that aged APP/PS1 mice can well replicate cognitive and noncognitive behavioral abnormalities, hippocampal atrophy, and neuronal and astrocyte degeneration in AD patients, to enable more objective and refined preclinical evaluation of therapeutic drugs and strategies for AD treatment.

  20. Vegetable Intake in College-Aged Adults Is Explained by Oral Sensory Phenotypes and TAS2R38 Genotype

    PubMed Central

    Hayes, John E.; Davidson, Andrew C.; Kidd, Judith R.; Kidd, Kenneth K.; Bartoshuk, Linda M.

    2010-01-01

    Taste and oral sensations vary in humans. Some of this variation has a genetic basis, and two commonly measured phenotypes are the bitterness of propylthiouracil (PROP) and the number of fungiform papillae on the anterior tongue. While the genetic control of fungiform papilla is unclear, PROP bitterness associates with allelic variation in the taste receptor gene, TAS2R38. The two common alleles are AVI and PAV (proline, alanine, valine, and isoleucine); AVI/AVI homozygotes taste PROP as less bitter than heterozygous or homozygous PAV carriers. In this laboratory-based study, we determined whether taste of a bitter probe (quinine) and vegetable intake varied by taste phenotypes and TAS2R38 genotype in healthy adults (mean age=26 years). Vegetable intake was assessed via two validated, complementary methods: food records (Food Pyramid servings standardized to energy intake) and food frequency questionnaire (general intake question and composite vegetable groups). Quinine bitterness varied with phenotypes but not TAS2R38; quinine was more bitter to those who tasted PROP as more bitter or had more papillae. Nontasters by phenotype or genotype reported greater consumption of vegetables, regardless of type (i.e., the effect generalized to all vegetables and was not restricted to those typically thought of as being bitter). Furthermore, nontasters with more papillae reported greater vegetable consumption than nontasters with fewer papillae, suggesting that when bitterness does not predominate, more papillae enhance vegetable liking. These findings suggest that genetic variation in taste, measured by multiple phenotypes or TAS2R38 genotype, can explain differences in overall consumption of vegetables, and this was not restricted to vegetables that are predominantly bitter. PMID:21157576

  1. Haptoglobin Phenotype Among Arab Patients With Mental Disorders.

    PubMed

    Armaly, Zaher; Farhat, Kamal; Kinaneh, Safa; Farah, Joseph

    2018-03-01

    Depression, schizophrenia and panic disorder are common mental disorders in the community and hospitalized patients. These mental disorders negatively affect life quality and even expectancy of life. Haptoglobin (Hp) phenotype (Hp 1-1, 1-2, or 2-2) is associated with risk for cardiovascular diseases, but its association with psychiatric disorders, a growing concern in the modern society, has not been studied thoroughly. The aim of the study was to examine whether Hp phenotype is associated with common mental disorders such as depression, schizophrenia, and panic disorder. The study included 92 Arab patients with mental disorders, and among them 44 suffered from schizophrenia (mean age 39 ± 1.5 years), 17 from depression (mean age 44.5 ± 3.1 years), 31 from panic disorder (mean age of 44.9 ± 2.7 years), and 206 healthy Arab control subjects with a mean age of 42.6 ± 0.9 years. Beck's depression inventory assessment and Hamilton depression scale were administered for depression and panic disorder diagnosis. Schizophrenia was evaluated with positive and negative affect schedule (Panas) test. All mental disorders were evaluated by clinical review. Blood analysis for Hp phenotype was performed. Diagnosis was made using the Diagnostic and Statistical Manual of Mental Disorders axis to correlate depression with Hp phenotype. In mentally healthy controls, 10.7% were Hp 1-1, 38.8% Hp 2-1, and 50.5% Hp 2-2. In patients with the studied psychiatric disorders, Hp phenotype was comparable to healthy subjects; 8.7% were Hp 1-1, 50% Hp 2-1, and 41.3% Hp 2-2. When Hp phenotyping was analyzed in the psychiatric subgroups, Hp 2-1 was more common among depressed and schizophrenic patients, as compared with healthy subjects (58.8% and 52.3% vs. 38.8%). In patients who suffer from panic disorder, Hp phenotype distribution was 6.5% Hp 1-1, 41.9% Hp 2-1, and 51.6% Hp 2-2, suggesting a lower prevalence among Hp 1-1 phenotype. Arab patients who carry Hp 2-1 phenotype may be at risk to

  2. NF-κB activation impairs somatic cell reprogramming in ageing.

    PubMed

    Soria-Valles, Clara; Osorio, Fernando G; Gutiérrez-Fernández, Ana; De Los Angeles, Alejandro; Bueno, Clara; Menéndez, Pablo; Martín-Subero, José I; Daley, George Q; Freije, José M P; López-Otín, Carlos

    2015-08-01

    Ageing constitutes a critical impediment to somatic cell reprogramming. We have explored the regulatory mechanisms that constitute age-associated barriers, through derivation of induced pluripotent stem cells (iPSCs) from individuals with premature or physiological ageing. We demonstrate that NF-κB activation blocks the generation of iPSCs in ageing. We also show that NF-κB repression occurs during cell reprogramming towards a pluripotent state. Conversely, ageing-associated NF-κB hyperactivation impairs the generation of iPSCs by eliciting the reprogramming repressor DOT1L, which reinforces senescence signals and downregulates pluripotency genes. Genetic and pharmacological NF-κB inhibitory strategies significantly increase the reprogramming efficiency of fibroblasts from Néstor-Guillermo progeria syndrome and Hutchinson-Gilford progeria syndrome patients, as well as from normal aged donors. Finally, we demonstrate that DOT1L inhibition in vivo extends lifespan and ameliorates the accelerated ageing phenotype of progeroid mice, supporting the interest of studying age-associated molecular impairments to identify targets of rejuvenation strategies.

  3. Relation Between Motility, Accelerated Aging and Gene Expression in Selected Drosophila Strains under Hypergravity Conditions

    NASA Astrophysics Data System (ADS)

    Serrano, Paloma; van Loon, Jack J. W. A.; Medina, F. Javier; Herranz, Raúl

    2013-02-01

    Motility and aging in Drosophila have proven to be highly modified under altered gravity conditions (both in space and ground simulation facilities). In order to find out how closely connected they are, five strains with altered geotactic response or survival rates were selected and exposed to an altered gravity environment of 2 g. By analysing the different motile and behavioural patterns and the median survival rates, we show that altered gravity leads to changes in motility, which will have a negative impact on the flies' survival. Previous results show a differential gene expression between sessile samples and adults and confirm that environmentally-conditioned behavioural patterns constrain flies' gene expression and life span. Therefore, hypergravity is considered an environmental stress factor and strains that do not respond to this new environment experience an increment in motility, which is the major cause for the observed increased mortality also under microgravity conditions. The neutral-geotaxis selected strain (strain M) showed the most severe phenotype, unable to respond to variations in the gravitational field. Alternatively, the opposite phenotype was observed in positive-geotaxis and long-life selected flies (strains B and L, respectively), suggesting that these populations are less sensitive to alterations in the gravitational load. We conclude that the behavioural response has a greater contribution to aging than the modified energy consumption in altered gravity environments.

  4. Aging and failure mode of electrochemical double layer capacitors during accelerated constant load tests

    NASA Astrophysics Data System (ADS)

    Kötz, R.; Ruch, P. W.; Cericola, D.

    Electrochemical double layer capacitors of the BCAP0350 type (Maxwell Technologies) were tested under constant load conditions at different voltages and temperatures. The aging of the capacitors was monitored during the test in terms of capacitance, internal resistance and leakage current. Aging was significantly accelerated by elevated temperature or increased voltage. Only for extreme conditions at voltages of 3.5 V or temperatures above 70 °C the capacitors failed due to internal pressure build-up. No other failure events such as open circuit or short circuit were detected. Impedance measurements after the tests showed increased high frequency resistance, an increased distributed resistance and most likely an increase in contact resistance between electrode and current collector together with a loss of capacitance. Capacitors aged at elevated voltages (3.3 V) exhibited a tilting of the low frequency component, which implies an increase in the heterogeneity of the electrode surface. This feature was not observed upon aging at elevated temperatures (70 °C).

  5. BENCHMARK ACCELERATED AGING OF HARVESTED HYPALON/EPR AND CSPE/XLPE POWER AND I&C CABLE IN NUCLEAR POWER PLANTS

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Duckworth, Robert C; Fifield, Dr Leonard S

    As part of the Light Water Reactor and Sustainability (LWRS) program in the U.S. Department of Energy (DOE) Office of Nuclear Energy, material aging and degradation research is currently geared to support the long-term operation of existing nuclear power plants (NPPs) as they move beyond their initial 40 year licenses. The goal of this research is to provide information so that NPPs can develop aging management programs (AMPs) to address replacement and monitoring needs as they look to operate for 20 years, and in some cases 40 years, beyond their initial operating lifetimes. For cable insulation and jacket materials thatmore » support instrument, control, and safety systems, accelerated aging data are needed to determine priorities in cable aging management programs. Before accelerated thermal and radiation aging of harvested, representative cable insulation and jacket materials, the benchmark performance of a new test capability at Oak Ridge National Laboratory (ORNL) was evaluated for temperatures between 70 and 135 C, dose rates between 100 and 500 Gy/h, and accumulated doses up to 20 kGy, Samples that were characterized and are representative of current materials in use were harvested from the Callaway NPP near Fulton, Missouri, and the San Onofre NPP north of San Diego, California. From the Callaway NPP, a multiconductor control rod cable manufactured by Boston Insulated Wire (BIW), with a Hypalon/ chorolosulfonated polyethylene (CSPE) jacket and ethylene-propylene rubber (EPR) insulation, was harvested from the auxiliary space during a planned outage in 2013. This cable was placed into service when the plant was started in 1984. From the San Onofre NPP, a Rockbestos Firewall III (FRIII) cable with a Hypalon/ CSPE jacket with cross-linked polyethylene (XLPE) insulation was harvested from an on-site, climate-controlled storage area. This conductor, which was never placed into service, was procured around 2007 in anticipation of future operation that did not

  6. Cardiac and Carotid Markers Link With Accelerated Brain Atrophy: The AGES-Reykjavik Study (Age, Gene/Environment Susceptibility-Reykjavik).

    PubMed

    Sabayan, Behnam; van Buchem, Mark A; Sigurdsson, Sigurdur; Zhang, Qian; Meirelles, Osorio; Harris, Tamara B; Gudnason, Vilmundur; Arai, Andrew E; Launer, Lenore J

    2016-11-01

    Pathologies in the heart-brain axis might, independently or in combination, accelerate the process of brain parenchymal loss. We aimed to investigate the association of serum N-terminal brain natriuretic peptide (NT-proBNP), as a marker of cardiac dysfunction, and carotid intima media thickness (CIMT), as a marker of carotid atherosclerosis burden, with structural brain changes. In the longitudinal population-based AGES-Reykjavik study (Age, Gene/Environment Susceptibility-Reykjavik), we included 2430 subjects (mean age, 74.6 years; 41.4% men) with baseline data on NT-proBNP and CITM (assessed by ultrasound imaging). Participants underwent a high-resolution brain magnetic resonance imaging at baseline and 5 years later to assess total brain (TBV), gray matter, and white matter volumes. Each unit higher log-transformed NT-proBNP was associated with 3.6 mL (95% confidence interval [CI], -6.0 to -1.1) decline in TBV and 3.5 mL (95% CI, -5.7 to -1.3) decline in gray matter volume. Likewise, each millimeter higher CIMT was associated with 10.8 mL (95% CI, -17.3 to -4.2) decline in TBV and 8.6 mL (95% CI, -14.4 to -2.8) decline in gray matter volume. There was no association between NT-proBNP and CIMT and changes in white matter volume. Compared with participants with low NT-proBNP and CIMT, participants with both high NT-proBNP and CIMT had 3.8 mL (95% CI, -6.0 to -1.6) greater decline in their TBV and 4 mL (95% CI, -6.0 to -2.0) greater decline in GMW. These associations were independent of sociodemographic and cardiovascular factors. Older subjects with both cardiac dysfunction and carotid atherosclerosis are at an increased risk for brain parenchymal loss. Accumulated pathologies in the heart-brain axis might accelerate brain atrophy. © 2016 American Heart Association, Inc.

  7. Shear banding leads to accelerated aging dynamics in a metallic glass

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Küchemann, Stefan; Liu, Chaoyang; Dufresne, Eric M.

    Traditionally, strain localization in metallic glasses is related to the thickness of the shear defect, which is confined to the nanometer scale. In this study, using site-specific x-ray photon correlation spectroscopy (XPCS), we reveal significantly accelerated relaxation dynamics around a shear band in a metallic glass at a length scale that is orders of magnitude larger than the defect itself. The relaxation time in the shear-band vicinity is up to ten-times smaller compared to the as-cast matrix, and the relaxation dynamics occurs in a characteristic three-stage aging response that manifests itself in the temperature-dependent shape parameter known from classical stretchedmore » exponential relaxation dynamics of disordered materials. We demonstrate that the time-dependent correlation functions describing the aging at different temperatures can be captured and collapsed using simple scaling functions. Finally, these insights highlight how an ubiquitous nano-scale strain-localization mechanism in metallic glasses leads to a fundamental change of the relaxation dynamics at the mesoscale.« less

  8. Shear banding leads to accelerated aging dynamics in a metallic glass

    DOE PAGES

    Küchemann, Stefan; Liu, Chaoyang; Dufresne, Eric M.; ...

    2018-01-11

    Traditionally, strain localization in metallic glasses is related to the thickness of the shear defect, which is confined to the nanometer scale. In this study, using site-specific x-ray photon correlation spectroscopy (XPCS), we reveal significantly accelerated relaxation dynamics around a shear band in a metallic glass at a length scale that is orders of magnitude larger than the defect itself. The relaxation time in the shear-band vicinity is up to ten-times smaller compared to the as-cast matrix, and the relaxation dynamics occurs in a characteristic three-stage aging response that manifests itself in the temperature-dependent shape parameter known from classical stretchedmore » exponential relaxation dynamics of disordered materials. We demonstrate that the time-dependent correlation functions describing the aging at different temperatures can be captured and collapsed using simple scaling functions. Finally, these insights highlight how an ubiquitous nano-scale strain-localization mechanism in metallic glasses leads to a fundamental change of the relaxation dynamics at the mesoscale.« less

  9. Effect of mouthwash and accelerated aging on the color stability of esthetic restorative materials.

    PubMed

    Lee, Y K; El Zawahry, M; Noaman, K M; Powers, J M

    2000-06-01

    To evaluate the color stability of esthetic restorative materials after immersion in mouthwashes and accelerated aging. Compomers and resin-based composites (RBC) were measured at baseline and repeatedly after immersion in three kinds of mouthwash (Listerine, Peridex, Rembrandt Age Defying) for 24 hrs and 7 days, and after aging for 150 kJ/m2. Color was measured according to CIE L*a*b* color scale on a reflection spectrophotometer. After immersion for 7 days, the mouthwash groups did not produce significantly higher color changes than the distilled water group, except with some mouthwashes used with Tetric-Ceram. After immersion for 7 days and aging for 150 kJ/m2, the mouthwash groups did not produce significantly higher color changes than the distilled water group. Aging in weathering chamber produced color change (deltaE*) of 1.1-3.9, which was mainly influenced by the material. With some exceptions, the color changes from immersion of the RBCs and compomers in mouthwashes were not perceptible (deltaE*<3.3).

  10. Effects of accelerated ageing on viability, leachate exudation, and fatty acid content of Dalbergia sissoo Roxb

    Treesearch

    R.C. Thapliyal; K.F. Connor

    1997-01-01

    Accelerated ageing of seeds of Dalbergia sissoo Roxb., a multi-purpose tropical legume tree, was effective as a vigour test only at temperatures in excess of 43 deg C for 72 h. Increased leakage of solutes accompanied the decrease in viability, but there was no relationship between seed size and conductivity. Analyses of D. sissoo...

  11. Analysis of the microstructure and mechanical performance of composite resins after accelerated artificial aging.

    PubMed

    De Oliveira Daltoé, M; Lepri, C Penazzo; Wiezel, J Guilherme G; Tornavoi, D Cremonezzi; Agnelli, J A Marcondes; Reis, A Cândido Dos

    2013-03-01

    Researches that assess the behavior of dental materials are important for scientific and industrial development especially when they are tested under conditions that simulate the oral environment, so this work analyzed the compressive strength and microstructure of three composite resins subjected to accelerated artificial aging (AAA). Three composites resins of 3M (P90, P60 and Z100) were analyzed and were obtained 16 specimens for each type (N.=48). Half of each type were subjected to UV-C system AAA and then were analyzed the surfaces of three aged specimens and three not aged of each type through the scanning electron microscope (SEM). After, eight specimens of each resin, aged and not aged, were subjected to compression test. After statistical analysis of compressive strength values, it was found that there was difference between groups (α <0.05). The resin specimens aged P60 presented lower values of compressive strength statistically significant when compared to the not subject to the AAA. For the other composite resins, there was no difference, regardless of aging, a fact confirmed by SEM. The results showed that the AAA influenced the compressive strength of the resin aged P60; confirmed by surface analysis by SEM, which showed greater structural disarrangement on surface material.

  12. Genome-Wide Identification of Regulatory Sequences Undergoing Accelerated Evolution in the Human Genome.

    PubMed

    Dong, Xinran; Wang, Xiao; Zhang, Feng; Tian, Weidong

    2016-10-01

    Accelerated evolution of regulatory sequence can alter the expression pattern of target genes, and cause phenotypic changes. In this study, we used DNase I hypersensitive sites (DHSs) to annotate putative regulatory sequences in the human genome, and conducted a genome-wide analysis of the effects of accelerated evolution on regulatory sequences. Working under the assumption that local ancient repeat elements of DHSs are under neutral evolution, we discovered that ∼0.44% of DHSs are under accelerated evolution (ace-DHSs). We found that ace-DHSs tend to be more active than background DHSs, and are strongly associated with epigenetic marks of active transcription. The target genes of ace-DHSs are significantly enriched in neuron-related functions, and their expression levels are positively selected in the human brain. Thus, these lines of evidences strongly suggest that accelerated evolution on regulatory sequences plays important role in the evolution of human-specific phenotypes. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  13. Mechanisms of lung aging.

    PubMed

    Brandenberger, Christina; Mühlfeld, Christian

    2017-03-01

    Lung aging is associated with structural remodeling, a decline of respiratory function and a higher susceptibility to acute and chronic lung diseases. Individual factors that modulate pulmonary aging include basic genetic configuration, environmental exposure, life-style and biography of systemic diseases. However, the actual aging of the lung takes place in pulmonary resident cells and is closely linked to aging of the immune system (immunosenescence). Therefore, this article reviews the current knowledge about the impact of aging on pulmonary cells and the immune system, without analyzing those factors that may accelerate the aging process in depth. Hallmarks of aging include alterations at molecular, cellular and cell-cell interaction levels. Because of the great variety of cell types in the lung, the consequences of aging display a broad spectrum of phenotypes. For example, aging is associated with more collagen and less elastin production by fibroblasts, thus increasing pulmonary stiffness and lowering compliance. Decreased sympathetic airway innervation may increase the constriction status of airway smooth muscle cells. Aging of resident and systemic immune cells leads to a pro-inflammatory milieu and reduced capacity of fighting infectious diseases. The current review provides an overview of cellular changes occurring with advancing age in general and in several cell types of the lung as well as of the immune system. Thereby, this survey not only aims at providing a better understanding of the mechanisms of pulmonary aging but also to identify gaps in knowledge that warrant further investigations.

  14. GPU-Accelerated Molecular Modeling Coming Of Age

    PubMed Central

    Stone, John E.; Hardy, David J.; Ufimtsev, Ivan S.

    2010-01-01

    Graphics processing units (GPUs) have traditionally been used in molecular modeling solely for visualization of molecular structures and animation of trajectories resulting from molecular dynamics simulations. Modern GPUs have evolved into fully programmable, massively parallel co-processors that can now be exploited to accelerate many scientific computations, typically providing about one order of magnitude speedup over CPU code and in special cases providing speedups of two orders of magnitude. This paper surveys the development of molecular modeling algorithms that leverage GPU computing, the advances already made and remaining issues to be resolved, and the continuing evolution of GPU technology that promises to become even more useful to molecular modeling. Hardware acceleration with commodity GPUs is expected to benefit the overall computational biology community by bringing teraflops performance to desktop workstations and in some cases potentially changing what were formerly batch-mode computational jobs into interactive tasks. PMID:20675161

  15. Ubiquitin over-expression phenotypes and ubiquitin gene molecular misreading during aging in Drosophila melanogaster

    PubMed Central

    Hoe, Nicholas; Huang, Chung M.; Landis, Gary; Verhage, Marian; Ford, Daniel; Yang, Junsheng; van Leeuwen, Fred W.; Tower, John

    2011-01-01

    Molecular Misreading (MM) is the inaccurate conversion of genomic information into aberrant proteins. For example, when RNA polymerase II transcribes a GAGAG motif it synthesizes at low frequency RNA with a two-base deletion. If the deletion occurs in a coding region, translation will result in production of misframed proteins. During mammalian aging, misframed versions of human amyloid precursor protein (hApp) and ubiquitin (hUbb) accumulate in the aggregates characteristic of neurodegenerative diseases, suggesting dysfunctional degradation or clearance. Here cDNA clones encoding wild-type hUbb and the frame-shifted version hUbb+1 were expressed in transgenic Drosophila using the doxycycline-regulated system. Misframed proteins were abundantly produced, both from the transgenes and from endogenous Drosophila ubiquitin-encoding genes, and their abundance increased during aging in whole-fly extracts. Over-expression of wild-type hUbb, but not hUbb+1, was toxic during fly development. In contrast, when over-expressed specifically in adult flies, hUbb+1 caused small decreases in life span, whereas hUbb was associated with small increases, preferentially in males. The data suggest that MM occurs in Drosophila and that the resultant misframed proteins accumulate with age. MM of the ubiquitin gene can produce alternative ubiquitin gene products with different and sometimes opposing phenotypic effects. PMID:21415465

  16. Mice over-expressing BDNF in forebrain neurons develop an altered behavioral phenotype with age.

    PubMed

    Weidner, Kate L; Buenaventura, Diego F; Chadman, Kathryn K

    2014-07-15

    Evidence from clinical studies suggests that abnormal activity of brain derived neurotrophic factor (BDNF) contributes to the pathogenesis of autism spectrum disorders (ASDs). A genetically modified line of mice over-expressing a BDNF transgene in forebrain neurons was used to investigate if this mutation leads to changes in behavior consistent with ASD. The mice used in these experiments were behaviorally tested past 5 months of age when spontaneous seizures were evident. These seizures were not observed in age-matched wildtype (WT) mice or younger mice from this transgenic line. The BDNF mice in these experiments weighed less than their WT littermates. The BDNF transgenic (BDNF-tg) mice demonstrated similar levels of sociability in the social approach test. Conversely, the BDNF-tg mice demonstrated less obsessive compulsive-like behavior in the marble burying test, less anxiety-like behavior in the elevated plus maze test, and less depressive-like behavior in the forced swim test. Changes in behavior were found in these older mice that have not been observed in younger mice from this transgenic line, which may be due to the development of seizures as the mice age. These mice do not have an ASD phenotype but may be useful to study adult onset epilepsy. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. SIRT1, 2, 3 protect mouse oocytes from postovulatory aging.

    PubMed

    Zhang, Teng; Zhou, Yang; Li, Li; Wang, Hong-Hui; Ma, Xue-Shan; Qian, Wei-Ping; Shen, Wei; Schatten, Heide; Sun, Qing-Yuan

    2016-04-01

    The quality of metaphase II oocytes will undergo a time-dependent deterioration following ovulation as the result of the oocyte aging process. In this study, we determined that the expression of sirtuin family members (SIRT1, 2, 3) was dramatically reduced in mouse oocytes aged in vivo or in vitro. Increased intracellular ROS was observed when SIRT1, 2, 3 activity was inhibited. Increased frequency of spindle defects and disturbed distribution of mitochondria were also observed in MII oocytes aged in vitro after treatment with Nicotinamide (NAM), indicating that inhibition of SIRT1, 2, 3 may accelerate postovulatory oocyte aging. Interestingly, when MII oocytes were exposed to caffeine, the decline of SIRT1, 2, 3 mRNA levels was delayed and the aging-associated defective phenotypes could be improved. The results suggest that the SIRT1, 2, 3 pathway may play a potential protective role against postovulatory oocyte aging by controlling ROS generation.

  18. Leveraging Collaborative Filtering to Accelerate Rare Disease Diagnosis

    PubMed Central

    Shen, Feichen; Liu, Sijia; Wang, Yanshan; Wang, Liwei; Afzal, Naveed; Liu, Hongfang

    2017-01-01

    In the USA, rare diseases are defined as those affecting fewer than 200,000 patients at any given time. Patients with rare diseases are frequently misdiagnosed or undiagnosed which may due to the lack of knowledge and experience of care providers. We hypothesize that patients’ phenotypic information available in electronic medical records (EMR) can be leveraged to accelerate disease diagnosis based on the intuition that providers need to document associated phenotypic information to support the diagnosis decision, especially for rare diseases. In this study, we proposed a collaborative filtering system enriched with natural language processing and semantic techniques to assist rare disease diagnosis based on phenotypic characterization. Specifically, we leveraged four similarity measurements with two neighborhood algorithms on 2010-2015 Mayo Clinic unstructured large patient cohort and evaluated different approaches. Preliminary results demonstrated that the use of collaborative filtering with phenotypic information is able to stratify patients with relatively similar rare diseases. PMID:29854225

  19. Leveraging Collaborative Filtering to Accelerate Rare Disease Diagnosis.

    PubMed

    Shen, Feichen; Liu, Sijia; Wang, Yanshan; Wang, Liwei; Afzal, Naveed; Liu, Hongfang

    2017-01-01

    In the USA, rare diseases are defined as those affecting fewer than 200,000 patients at any given time. Patients with rare diseases are frequently misdiagnosed or undiagnosed which may due to the lack of knowledge and experience of care providers. We hypothesize that patients' phenotypic information available in electronic medical records (EMR) can be leveraged to accelerate disease diagnosis based on the intuition that providers need to document associated phenotypic information to support the diagnosis decision, especially for rare diseases. In this study, we proposed a collaborative filtering system enriched with natural language processing and semantic techniques to assist rare disease diagnosis based on phenotypic characterization. Specifically, we leveraged four similarity measurements with two neighborhood algorithms on 2010-2015 Mayo Clinic unstructured large patient cohort and evaluated different approaches. Preliminary results demonstrated that the use of collaborative filtering with phenotypic information is able to stratify patients with relatively similar rare diseases.

  20. Towards an Age-Phenome Knowledge-base

    PubMed Central

    2011-01-01

    Background Currently, data about age-phenotype associations are not systematically organized and cannot be studied methodically. Searching for scientific articles describing phenotypic changes reported as occurring at a given age is not possible for most ages. Results Here we present the Age-Phenome Knowledge-base (APK), in which knowledge about age-related phenotypic patterns and events can be modeled and stored for retrieval. The APK contains evidence connecting specific ages or age groups with phenotypes, such as disease and clinical traits. Using a simple text mining tool developed for this purpose, we extracted instances of age-phenotype associations from journal abstracts related to non-insulin-dependent Diabetes Mellitus. In addition, links between age and phenotype were extracted from clinical data obtained from the NHANES III survey. The knowledge stored in the APK is made available for the relevant research community in the form of 'Age-Cards', each card holds the collection of all the information stored in the APK about a particular age. These Age-Cards are presented in a wiki, allowing community review, amendment and contribution of additional information. In addition to the wiki interaction, complex searches can also be conducted which require the user to have some knowledge of database query construction. Conclusions The combination of a knowledge model based repository with community participation in the evolution and refinement of the knowledge-base makes the APK a useful and valuable environment for collecting and curating existing knowledge of the connections between age and phenotypes. PMID:21651792

  1. Age-related cognitive decline coincides with accelerated volume loss of the dorsal but not ventral hippocampus in mice.

    PubMed

    Reichel, J M; Bedenk, B T; Czisch, M; Wotjak, C T

    2017-01-01

    Even in the absence of neurodegenerative diseases, progressing age often coincides with cognitive decline and morphological changes. However, longitudinal studies that directly link these two processes are missing. In this proof-of-concept study we therefore performed repeated within-subject testing of healthy male R26R mice in a spatial learning task in combination with manganese-enhanced volumetric MRI analyses at the ages of 8, 16, and 24 months. We grouped the mice into good and poor performers (n = 6, each), based on their spatial learning abilities at the age of 24 months. Using this stratification, we failed to detect a priori volume differences, but observed a significant decrease in total hippocampal volume over time for both groups. Interestingly, this volume decrease was specific for the dorsal hippocampus and significantly accelerated in poor performers between 16 and 24 months of age. This is the first time that individual changes in hippocampal volume were traced alongside cognitive performance within the same subjects over 1½ years. Our study points to a causal link between volume loss of the dorsal hippocampus and cognitive impairments. In addition, it suggests accelerated degenerative processes rather than a priori volume differences as determining trajectories of age-related cognitive decline. Despite the relatively small sample sizes, the strong behavioral and moderate morphological alterations demonstrate the general feasibility of longitudinal studies of age-related decline in cognition and hippocampus integrity. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  2. HFE p.H63D polymorphism does not influence ALS phenotype and survival.

    PubMed

    Chiò, Adriano; Mora, Gabriele; Sabatelli, Mario; Caponnetto, Claudia; Lunetta, Christian; Traynor, Bryan J; Johnson, Janel O; Nalls, Mike A; Calvo, Andrea; Moglia, Cristina; Borghero, Giuseppe; Monsurrò, Maria Rosaria; La Bella, Vincenzo; Volanti, Paolo; Simone, Isabella; Salvi, Fabrizio; Logullo, Francesco O; Nilo, Riva; Giannini, Fabio; Mandrioli, Jessica; Tanel, Raffaella; Murru, Maria Rita; Mandich, Paola; Zollino, Marcella; Conforti, Francesca L; Penco, Silvana; Brunetti, Maura; Barberis, Marco; Restagno, Gabriella

    2015-10-01

    It has been recently reported that the p.His63Asp polymorphism of the HFE gene accelerates disease progression both in the SOD1 transgenic mouse and in amyotrophic lateral sclerosis (ALS) patients. We have evaluated the effect of HFE p.His63Asp polymorphism on the phenotype in 1351 Italian ALS patients (232 of Sardinian ancestry). Patients were genotyped for the HFE p.His63Asp polymorphism (CC, GC, and GG). All patients were also assessed for C9ORF72, TARDBP, SOD1, and FUS mutations. Of the 1351 ALS patients, 363 (29.2%) were heterozygous (GC) for the p.His63Asp polymorphism and 30 (2.2%) were homozygous for the minor allele (GG). Patients with CC, GC, and GG polymorphisms did not significantly differ by age at onset, site of onset of symptoms, and survival; however, in SOD1 patients with CG or GG polymorphism had a significantly longer survival than those with a CC polymorphism. Differently from what observed in the mouse model of ALS, the HFE p.His63Asp polymorphism has no effect on ALS phenotype in this large series of Italian ALS patients. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Relationship between endophenotype and phenotype in ADHD

    PubMed Central

    Rommelse, Nanda NJ; Altink, Marieke E; Martin, Neilson C; Buschgens, Cathelijne JM; Faraone, Stephen V; Buitelaar, Jan K; Sergeant, Joseph A; Oosterlaan, Jaap

    2008-01-01

    Background It has been hypothesized that genetic and environmental factors relate to psychiatric disorders through the effect of intermediating, vulnerability traits called endophenotypes. The study had a threefold aim: to examine the predictive validity of an endophenotypic construct for the ADHD diagnosis, to test whether the magnitude of group differences at the endophenotypic and phenotypic level is comparable, and to investigate whether four factors (gender, age, IQ, rater bias) have an effect (moderation or mediation) on the relation between endophenotype and phenotype. Methods Ten neurocognitive tasks were administered to 143 children with ADHD, 68 non-affected siblings, and 120 control children (first-borns) and 132 children with ADHD, 78 non-affected siblings, and 113 controls (second-borns) (5 – 19 years). The task measures have been investigated previously for their endophenotypic viability and were combined to one component which was labeled 'the endophenotypic construct': one measure representative of endophenotypic functioning across several domains of functioning. Results The endophenotypic construct classified children with moderate accuracy (about 50% for each of the three groups). Non-affected children differed as much from controls at the endophenotypic as at the phenotypic level, but affected children displayed a more severe phenotype than endophenotype. Although a potentially moderating effect (age) and several mediating effects (gender, age, IQ) were found affecting the relation between endophenotypic construct and phenotype, none of the effects studied could account for the finding that affected children had a more severe phenotype than endophenotype. Conclusion Endophenotypic functioning is moderately predictive of the ADHD diagnosis, though findings suggest substantial overlap exists between endophenotypic functioning in the groups of affected children, non-affected siblings, and controls. Results suggest other factors may be crucial and

  4. Advanced Glycation End Products Enhance Macrophages Polarization into M1 Phenotype through Activating RAGE/NF-κB Pathway

    PubMed Central

    Jin, Xian; Yao, Tongqing; Zhou, Zhong'e; Zhu, Jian; Zhang, Song; Hu, Wei; Shen, Chengxing

    2015-01-01

    Atherosclerotic lesions are accelerated in patients with diabetes. M1 (classically activated in contrast to M2 alternatively activated) macrophages play key roles in the progression of atherosclerosis. Since advanced glycation end products (AGEs) are major pathogenic factors and active inflammation inducers in diabetes mellitus, this study assessed the effects of AGEs on macrophage polarization. The present study showed that AGEs significantly promoted macrophages to express IL-6 and TNF-α. M1 macrophage markers such as iNOS and surface markers including CD11c and CD86 were significantly upregulated while M2 macrophage markers such as Arg1 and CD206 remained unchanged after AGEs stimulation. AGEs significantly increased RAGE expression in macrophages and activated NF-κB pathway, and the aforementioned effects were partly abolished by administration of anti-RAGE antibody or NF-κB inhibitor PDTC. In conclusion, our results suggest that AGEs enhance macrophage differentiation into proinflammatory M1 phenotype at least partly via RAGE/NF-κB pathway activation. PMID:26114112

  5. Public health impact of accelerated immunization against rotavirus infection among children aged less than 6 months in the United States

    PubMed Central

    Weycker, Derek; Atwood, Mark Andrew; Standaert, Baudouin; Krishnarajah, Girishanthy

    2014-01-01

    We developed a cohort model to evaluate the expected public health impact of accelerated regimens for immunization against rotavirus gastroenteritis (RVGE). Alternative strategies for vaccination with the pentavalent human-bovine reassortant vaccine, Rotateq® (RV5, Merck) and the oral live attenuated human rotavirus vaccine, Rotarix® (RV1, GlaxoSmithKline Vaccines) were considered, including acceleration of the 1st dose only (by 2 weeks) as well as acceleration of the 1st (by 2 weeks) and subsequent doses (by up to 10 weeks). Assuming vaccine coverage levels consistent with current US clinical practice, accelerated regimens would be expected to reduce annual numbers of RVGE-related hospitalizations by 300–400, emergency department visits by 3000–4000, and outpatient visits by 3000–4000 (i.e., by 9–14%) among US children aged <6 months. Accordingly, accelerating the immunization of children against RVGE may yield substantive reductions in the number of RV-related encounters in US clinical practice. PMID:25424813

  6. Association between pain and the frailty phenotype in older men: longitudinal results from the Concord Health and Ageing in Men Project (CHAMP).

    PubMed

    Megale, Rodrigo Z; Ferreira, Manuela L; Ferreira, Paulo H; Naganathan, Vasi; Cumming, Robert; Hirani, Vasant; Waite, Louise M; Seibel, Markus J; Le Couteur, David G; Handelsman, David J; Blyth, Fiona M

    2018-05-01

    to determine whether pain increases the risk of developing the frailty phenotype and whether frailty increases the risk of developing chronic or intrusive pain, using longitudinal data. longitudinal data from the Concord Health and Ageing in Men Project (CHAMP), a prospective population based cohort study. a total of 1,705 men aged 70 years or older, living in an urban area of New South Wales, Australia. data on the presence of chronic pain (daily pain for at least 3 months), intrusive pain (pain causing moderate to severe interference with activities) and the criteria for the Cardiovascular Health Study (CHS) frailty phenotype were collected in three waves, from January 2005 to October 2013. Data on age, living arrangements, education, smoking status, alcohol consumption, body mass index, comorbidities, cognitive function, depressive symptoms and history of vertebral or hip fracture were also collected and included as covariates in the analyses. a total of 1,705 participants were included at baseline, of whom 1,332 provided data at the 2-year follow-up and 940 at the 5-year follow-up. Non-frail (robust and pre-frail) men who reported chronic pain were 1.60 (95% confidence interval (CI): 1.02-2.51, P = 0.039) times more likely to develop frailty at follow-up, compared to those with no pain. Intrusive pain did not significantly increase the risk of future frailty. Likewise, the frailty status was not associated with future chronic or intrusive pain in the adjusted analysis. the presence of chronic pain increases the risk of developing the frailty phenotype in community-dwelling older men.

  7. Benchmark Accelerated Aging of Harvested Hypalon/Epr and Cspe/Xlpe Power and I&C Cable in Nuclear Power Plants

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Duckworth, Robert C.; Frame, Emily; Fifield, Leonard S.

    As part of the Light Water Reactor and Sustainability (LWRS) program in the U.S. Department of Energy (DOE) Office of Nuclear Energy, material aging and degradation research is currently geared to support the long-term operation of existing nuclear power plants (NPPs) as they move beyond their initial 40 year licenses. The goal of this research is to provide information so that NPPs can develop aging management programs (AMPs) to address replacement and monitoring needs as they look to operate for 20 years, and in some cases 40 years, beyond their initial operating lifetimes. For cable insulation and jacket materials thatmore » support instrument, control, and safety systems, accelerated aging data are needed to determine priorities in cable aging management programs. Before accelerated thermal and radiation aging of harvested, representative cable insulation and jacket materials, the benchmark performance of a new test capability at Oak Ridge National Laboratory (ORNL) was evaluated for temperatures between 70 and 135°C, dose rates between 100 and 500 Gy/h, and accumulated doses up to 20 kGy, Samples that were characterized and are representative of current materials in use were harvested from the Callaway NPP near Fulton, Missouri, and the San Onofre NPP north of San Diego, California. From the Callaway NPP, a multiconductor control rod cable manufactured by Boston Insulated Wire (BIW), with a Hypalon/ chorolosulfonated polyethylene (CSPE) jacket and ethylene-propylene rubber (EPR) insulation, was harvested from the auxiliary space during a planned outage in 2013. This cable was placed into service when the plant was started in 1984. From the San Onofre NPP, a Rockbestos Firewall III (FRIII) cable with a Hypalon/ CSPE jacket with cross-linked polyethylene (XLPE) insulation was harvested from an on-site, climate-controlled storage area. This conductor, which was never placed into service, was procured around 2007 in anticipation of future operation that did not

  8. GPU-accelerated molecular modeling coming of age.

    PubMed

    Stone, John E; Hardy, David J; Ufimtsev, Ivan S; Schulten, Klaus

    2010-09-01

    Graphics processing units (GPUs) have traditionally been used in molecular modeling solely for visualization of molecular structures and animation of trajectories resulting from molecular dynamics simulations. Modern GPUs have evolved into fully programmable, massively parallel co-processors that can now be exploited to accelerate many scientific computations, typically providing about one order of magnitude speedup over CPU code and in special cases providing speedups of two orders of magnitude. This paper surveys the development of molecular modeling algorithms that leverage GPU computing, the advances already made and remaining issues to be resolved, and the continuing evolution of GPU technology that promises to become even more useful to molecular modeling. Hardware acceleration with commodity GPUs is expected to benefit the overall computational biology community by bringing teraflops performance to desktop workstations and in some cases potentially changing what were formerly batch-mode computational jobs into interactive tasks. (c) 2010 Elsevier Inc. All rights reserved.

  9. Stepwise Distributed Open Innovation Contests for Software Development: Acceleration of Genome-Wide Association Analysis

    PubMed Central

    Hill, Andrew; Loh, Po-Ru; Bharadwaj, Ragu B.; Pons, Pascal; Shang, Jingbo; Guinan, Eva; Lakhani, Karim; Kilty, Iain

    2017-01-01

    Abstract Background: The association of differing genotypes with disease-related phenotypic traits offers great potential to both help identify new therapeutic targets and support stratification of patients who would gain the greatest benefit from specific drug classes. Development of low-cost genotyping and sequencing has made collecting large-scale genotyping data routine in population and therapeutic intervention studies. In addition, a range of new technologies is being used to capture numerous new and complex phenotypic descriptors. As a result, genotype and phenotype datasets have grown exponentially. Genome-wide association studies associate genotypes and phenotypes using methods such as logistic regression. As existing tools for association analysis limit the efficiency by which value can be extracted from increasing volumes of data, there is a pressing need for new software tools that can accelerate association analyses on large genotype-phenotype datasets. Results: Using open innovation (OI) and contest-based crowdsourcing, the logistic regression analysis in a leading, community-standard genetics software package (PLINK 1.07) was substantially accelerated. OI allowed us to do this in <6 months by providing rapid access to highly skilled programmers with specialized, difficult-to-find skill sets. Through a crowd-based contest a combination of computational, numeric, and algorithmic approaches was identified that accelerated the logistic regression in PLINK 1.07 by 18- to 45-fold. Combining contest-derived logistic regression code with coarse-grained parallelization, multithreading, and associated changes to data initialization code further developed through distributed innovation, we achieved an end-to-end speedup of 591-fold for a data set size of 6678 subjects by 645 863 variants, compared to PLINK 1.07's logistic regression. This represents a reduction in run time from 4.8 hours to 29 seconds. Accelerated logistic regression code developed in this

  10. Colour-stability and gloss-retention of silorane and dimethacrylate composites with accelerated aging.

    PubMed

    Furuse, Adilson Y; Gordon, Kathryn; Rodrigues, Flávia P; Silikas, Nick; Watts, David C

    2008-11-01

    To evaluate the colour-stability and gloss-retention of silorane versus dimethacrylate composites exposed to accelerated aging from daylight radiation. Five disc-shaped specimens of photo-cured resin-composites were prepared and manually polished for each material (Filtek Silorane, Herculite XRV, Tetric Evoceram and QuiXfil). Colour and gloss were evaluated before and after periods (baseline, 24, 72, 120 and 192 h) of accelerated photo-aging in xenon light following ISO 7491:2000. Colour measurements were performed with a colourimeter according to the CIE-Lab colour-space. The colour change (DeltaE) for each time was calculated. The surface gloss was measured using a glossmeter. Results were evaluated using one-way ANOVA and Tukey tests (alpha=0.05). Correlations between logtime, DeltaE and gloss were evaluated using Pearson's correlation (alpha=0.05). Materials generally decreased in L and a and increased in b. The strong exception was Filtek Silorane which maintained a and b. DeltaE was found to be a positive linear function of logtime for all materials. Materials varied in the magnitude and rate of increase of DeltaE with logtime: QuiXfil>Tetric EvoCeram>(Filtek Silorane>or=Herculite XRV). DeltaE remained<3.3 for Filtek Silorane and Herculite XRV. Gloss was found to be a negative linear function of logtime. Gloss was maximal in the sequence: Filtek Silorane approximately Tetric EvoCeram>Herculite XRV>QuiXfil. Silorane gave the best overall performance in stability over time, compared to a set of representative dimethacrylate composites.

  11. Microstructural modifications induced by accelerated aging and lipid absorption in remelted and annealed UHMWPEs for total hip arthroplasty

    PubMed Central

    Puppulin, Leonardo; Zhu, Wenliang; Sugano, Nobuhiko

    2014-01-01

    Three types of commercially available ultra-high molecular weight polyethylene (UHMWPE) acetabular cups currently used in total hip arthroplasty have been studied by means of Raman micro-spectroscopy to unfold the microstructural modification induced by the oxidative degradation after accelerated aging with and without lipid absorption. The three investigated materials were produced by three different manufacturing procedures, as follows: irradiation followed by remelting, one-step irradiation followed by annealing, 3-step irradiation and annealing. Clear microstructural differences were observed in terms of phase contents (i.e. amorphous, crystalline and intermediate phase fraction). The three-step annealed material showed the highest crystallinity fraction in the bulk, while the remelted polyethylene is clearly characterized by the lowest content of crystalline phase and the highest content of amorphous phase. After accelerated aging either with or without lipids, the amount of amorphous phase decreased in all the samples as a consequence of the oxidation-induced recrystallization. The most remarkable variations of phase contents were detected in the remelted and in the single-step annealed materials. The presence of lipids triggered oxidative degradation especially in the remelted polyethylene. Such experimental evidence might be explained by the highest amount of amorphous phase in which lipids can be absorbed prior to accelerated aging. The results of these spectroscopic characterizations help to rationalize the complex effect of different irradiation and post-irradiation treatments on the UHMWPE microstructure and gives useful information on how significantly any single step of the manufacturing procedures might affect the oxidative degradation of the polymer. PMID:25179830

  12. Avoidance of accelerated aging in schizophrenia?: Clinical and biological characterization of an exceptionally high functioning individual.

    PubMed

    Palmer, Barton W; Moore, Raeanne C; Eyler, Lisa T; Pinto, Luz L; Saks, Elyn R; Jeste, Dilip V

    2018-06-01

    To determine the clinical and biological characteristics of an exceptionally high functioning index person (IP) with schizophrenia in her mid-50s, which may represent compensatory mechanisms, and potentially, avoidance of the accelerated aging typically associated with schizophrenia. IP, 11 other women with schizophrenia, and 11 non-psychiatric comparison (NC) women were assessed with standard ratings of psychopathology, neurocognitive function, decisional capacity, and functional brain imaging. IP was also compared to a sample of demographically similar NCs (N=45) and persons with schizophrenia (N=42) on a set of blood-based biomarkers of aging related to metabolic function, oxidative stress, and inflammation. IP's scores on working memory, and levels of brain activation during an affective face matching task in the left fusiform, right lingual, and left precentral gyri, exceeded NCs. IP was similar to NCs in severity of negative symptoms, most neurocognitive functions, decisional capacity, and brain activation in the left inferior occipital gyrus during a selective stopping task. IP's levels on 11 of 14 metabolic and inflammatory biomarkers of aging were better than NCs and the schizophrenia group. Although speculative, results suggest a possible model in which superior working memory permits a person to be aware of the potentially psychotic nature of a thought or perception, and adjust response accordingly. Compensatory overactivity of brain regions during affective processing may also reflect heightened meta-awareness in emotional situations. Biomarker levels raise the possibility that IP partially avoided the accelerated biological aging associated with schizophrenia. Published by Elsevier B.V.

  13. [Methods of high-throughput plant phenotyping for large-scale breeding and genetic experiments].

    PubMed

    Afonnikov, D A; Genaev, M A; Doroshkov, A V; Komyshev, E G; Pshenichnikova, T A

    2016-07-01

    Phenomics is a field of science at the junction of biology and informatics which solves the problems of rapid, accurate estimation of the plant phenotype; it was rapidly developed because of the need to analyze phenotypic characteristics in large scale genetic and breeding experiments in plants. It is based on using the methods of computer image analysis and integration of biological data. Owing to automation, new approaches make it possible to considerably accelerate the process of estimating the characteristics of a phenotype, to increase its accuracy, and to remove a subjectivism (inherent to humans). The main technologies of high-throughput plant phenotyping in both controlled and field conditions, their advantages and disadvantages, and also the prospects of their use for the efficient solution of problems of plant genetics and breeding are presented in the review.

  14. Hypervitaminosis D and premature aging: lessons learned from Fgf23 and Klotho mutant mice.

    PubMed

    Razzaque, Mohammed S; Lanske, Beate

    2006-07-01

    The essential role of low levels of vitamin D during aging is well documented. However, possible effects of high levels of vitamin D on the aging process are not yet clear. Recent in vivo genetic-manipulation studies have shown increased serum level of vitamin D and altered mineral-ion homeostasis in mice that lack either fibroblast growth factor 23 (Fgf23) or klotho (Kl) genes. These mice develop identical phenotypes consistent with premature aging. Elimination or reduction of vitamin-D activity from Fgf23 and Kl mutant mice, either by dietary restriction or genetic manipulation could rescue premature aging-like features and ectopic calcifications, resulting in prolonged survival of both mutants. Such in vivo experimental studies indicated that excessive vitamin-D activity and altered mineral-ion homeostasis could accelerate the aging process.

  15. Aroma profile and sensory characteristics of a sulfur dioxide-free mulberry (Morus nigra) wine subjected to non-thermal accelerating aging techniques.

    PubMed

    Tchabo, William; Ma, Yongkun; Kwaw, Emmanuel; Zhang, Haining; Xiao, Lulu; Tahir, Haroon Elrasheid

    2017-10-01

    The present study was undertaken to assess accelerating aging effects of high pressure, ultrasound and manosonication on the aromatic profile and sensorial attributes of aged mulberry wines (AMW). A total of 166 volatile compounds were found amongst the AMW. The outcomes of the investigation were presented by means of geometric mean (GM), cluster analysis (CA), principal component analysis (PCA), partial least squares regressions (PLSR) and principal component regression (PCR). GM highlighted 24 organoleptic attributes responsible for the sensorial profile of the AMW. Moreover, CA revealed that the volatile composition of the non-thermal accelerated aged wines differs from that of the conventional aged wines. Besides, PCA discriminated the AMW on the basis of their main sensorial characteristics. Furthermore, PLSR identified 75 aroma compounds which were mainly responsible for the olfactory notes of the AMW. Finally, the overall quality of the AMW was noted to be better predicted by PLSR than PCR. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. SAMP8 mice as a neuropathological model of accelerated brain aging and dementia: Toshio Takeda's legacy and future directions.

    PubMed

    Akiguchi, Ichiro; Pallàs, Mercè; Budka, Herbert; Akiyama, Haruhiko; Ueno, Masaki; Han, Jingxian; Yagi, Hideo; Nishikawa, Tomohumi; Chiba, Yoichi; Sugiyama, Hiroshi; Takahashi, Ryoya; Unno, Keiko; Higuchi, Keiichi; Hosokawa, Masanori

    2017-08-01

    Senescence accelerated mice P8 (SAMP8) show significant age-related deteriorations in memory and learning ability in accordance with early onset and rapid advancement of senescence. Brains of SAMP8 mice reveal an age-associated increase of PAS-positive granular structures in the hippocampal formation and astrogliosis in the brain stem and hippocampus. A spongy degeneration in the brain stem appears at 1 month of age and reaches a maximum at 4-8 months. In addition, clusters of activated microglia also appear around the vacuoles in the brain stem. β/A4(Aβ) protein-like immunoreactive granular structures are observed in various regions and increase in number markedly with age. Other age-associated histological changes include cortical atrophy, neuronal cell loss in locus coeruleus and lateral tegmental nuclei, intraneuronal accumulation of lipopigments in Purkinje cells and eosinophilic inclusion bodies in thalamic neurons. A blood-brain barrier dysfunction and astrogliosis are also prominent with advancing age in the hippocampus. These changes are generally similar to the pathomorphology of aging human brains and characterized by their association with some specific glioneuronal reactions. As for the hallmarks of Alzheimer brains, tau morphology has not yet been confirmed regardless of the age-related increase in phosphorylated tau in SAMP8 mice brains, but early age-related Aβ deposition in the hippocampus has recently been published. SAMP8 mice are, therefore, not only a senescence-accelerated model but also a promising model for Alzheimer's disease and other cognitive disorders. © 2017 Japanese Society of Neuropathology.

  17. Sarcopenic obesity and overall mortality: Results from the application of novel models of body composition phenotypes to the National Health and Nutrition Examination Survey 1999-2004.

    PubMed

    Van Aller, Carla; Lara, Jose; Stephan, Blossom C M; Donini, Lorenzo Maria; Heymsfield, Steven; Katzmarzyk, Peter T; Wells, Jonathan C K; Prado, Carla M; Siervo, Mario

    2018-02-15

    There is no consensus on the definition of sarcopenic obesity (SO), resulting in inconsistent associations of SO with mortality risk. We aim to evaluate association of dual energy x-ray absorptiometry (DXA) SO models with mortality risk in a US adult population (≥50 years). The study population consisted of 3577 participants aged 50 years and older from the 1999-2004 National Health and Nutrition and Examination Survey with mortality follow-up data through December 31, 2011. Difference in survival time in people with and without SO defined by three body composition DXA models (Model 1: body composition phenotype model; Model 2: Truncal Fat Mass (TrFM)/Appendicular Skeletal Muscle Mass (ASM) ratio model; Model 3: Fat Mass (FM)/Fat Free Mass (FFM) ratio). The differences between the models were assessed by the acceleration failure time model, and expressed as time ratios (TR). Participants age 50-70 years with SO had a significantly decreased survival time, according to the body composition phenotype model (TR: 0.92; 95% CI: 0.87-0.97), and TrFM/ASM ratio model (TR: 0.88; 95% CI: 0.81-0.95). The FM/FFM ratio model did not detect significant differences in survival time. Participants with SO aged 70 years and older did not have a significantly decreased survival time, according to all three models. A SO phenotype increases mortality risk in people of age 50-70 years, but not in people aged 70 years and older. The application of the body composition phenotype and the TrFM/ASM ratio models may represent useful diagnostic approaches to improve the prediction of disease and mortality risk. Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  18. The signaling pathways by which the Fas/FasL system accelerates oocyte aging.

    PubMed

    Zhu, Jiang; Lin, Fei-Hu; Zhang, Jie; Lin, Juan; Li, Hong; Li, You-Wei; Tan, Xiu-Wen; Tan, Jing-He

    2016-02-01

    In spite of great efforts, the mechanisms for postovulatory oocyte aging are not fully understood. Although our previous work showed that the FasL/Fas signaling facilitated oocyte aging, the intra-oocyte signaling pathways are unknown. Furthermore, the mechanisms by which oxidative stress facilitates oocyte aging and the causal relationship between Ca2+ rises and caspase-3 activation and between the cell cycle and apoptosis during oocyte aging need detailed investigations. Our aim was to address these issues by studying the intra-oocyte signaling pathways for Fas/FasL to accelerate oocyte aging. The results indicated that sFasL released by cumulus cells activated Fas on the oocyte by increasing reactive oxygen species via activating NADPH oxidase. The activated Fas triggered Ca2+ release from the endoplasmic reticulum by activating phospholipase C-γ pathway and cytochrome c pathway. The cytoplasmic Ca2+ rises activated calcium/calmodulin-dependent protein kinase II (CaMKII) and caspase-3. While activated CaMKII increased oocyte susceptibility to activation by inactivating maturation-promoting factor (MPF) through cyclin B degradation, the activated caspase-3 facilitated further Ca2+releasing that activates more caspase-3 leading to oocyte fragmentation. Furthermore, caspase-3 activation and fragmentation were prevented in oocytes with a high MPF activity, suggesting that an oocyte must be in interphase to undergo apoptosis.

  19. Cell and small animal models for phenotypic drug discovery.

    PubMed

    Szabo, Mihaly; Svensson Akusjärvi, Sara; Saxena, Ankur; Liu, Jianping; Chandrasekar, Gayathri; Kitambi, Satish S

    2017-01-01

    The phenotype-based drug discovery (PDD) approach is re-emerging as an alternative platform for drug discovery. This review provides an overview of the various model systems and technical advances in imaging and image analyses that strengthen the PDD platform. In PDD screens, compounds of therapeutic value are identified based on the phenotypic perturbations produced irrespective of target(s) or mechanism of action. In this article, examples of phenotypic changes that can be detected and quantified with relative ease in a cell-based setup are discussed. In addition, a higher order of PDD screening setup using small animal models is also explored. As PDD screens integrate physiology and multiple signaling mechanisms during the screening process, the identified hits have higher biomedical applicability. Taken together, this review highlights the advantages gained by adopting a PDD approach in drug discovery. Such a PDD platform can complement target-based systems that are currently in practice to accelerate drug discovery.

  20. Early Cognitive/Social Deficits and Late Motor Phenotype in Conditional Wild-Type TDP-43 Transgenic Mice.

    PubMed

    Alfieri, Julio A; Silva, Pablo R; Igaz, Lionel M

    2016-01-01

    Frontotemporal Dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two neurodegenerative diseases associated to mislocalization and aggregation of TAR DNA-binding protein 43 (TDP-43). To investigate in depth the behavioral phenotype associated with this proteinopathy, we used as a model transgenic (Tg) mice conditionally overexpressing human wild-type TDP 43 protein (hTDP-43-WT) in forebrain neurons. We previously characterized these mice at the neuropathological level and found progressive neurodegeneration and other features that evoke human TDP-43 proteinopathies of the FTD/ALS spectrum. In the present study we analyzed the behavior of mice at multiple domains, including motor, social and cognitive performance. Our results indicate that young hTDP-43-WT Tg mice (1 month after post-weaning transgene induction) present a normal motor phenotype compared to control littermates, as assessed by accelerated rotarod performance, spontaneous locomotor activity in the open field test and a mild degree of spasticity shown by a clasping phenotype. Analysis of social and cognitive behavior showed a rapid installment of deficits in social interaction, working memory (Y-maze test) and recognition memory (novel object recognition test) in the absence of overt motor abnormalities. To investigate if the motor phenotype worsen with age, we analyzed the behavior of mice after long-term (up to 12 months) transgene induction. Our results reveal a decreased performance on the rotarod test and in the hanging wire test, indicating a motor phenotype that was absent in younger mice. In addition, long-term hTDP-43-WT expression led to hyperlocomotion in the open field test. In sum, these results demonstrate a time-dependent emergence of a motor phenotype in older hTDP-43-WT Tg mice, recapitulating aspects of clinical FTD presentations with motor involvement in human patients, and providing a complementary animal model for studying TDP-43 proteinopathies.

  1. Auditory Phenotype of Smith-Magenis Syndrome.

    PubMed

    Brendal, Megan A; King, Kelly A; Zalewski, Christopher K; Finucane, Brenda M; Introne, Wendy; Brewer, Carmen C; Smith, Ann C M

    2017-04-14

    The purpose of this study was to describe the auditory phenotype of a large cohort with Smith-Magenis syndrome (SMS), a rare disorder including physical anomalies, cognitive deficits, sleep disturbances, and a distinct behavioral phenotype. Hearing-related data were collected for 133 individuals with SMS aged 1-49 years. Audiogram data (97 participants) were used for cross-sectional and longitudinal analyses. Caregivers completed a sound sensitivity survey for 98 individuals with SMS and a control group of 24 unaffected siblings. Nearly 80% of participants with interpretable audiograms (n = 76) had hearing loss, which was typically slight to mild in degree. When hearing loss type could be determined (40 participants), sensorineural hearing loss (48.1%) occurred most often in participants aged 11-49 years. Conductive hearing loss (35.2%) was typically observed in children aged 1-10 years. A pattern of fluctuating and progressive hearing decline was documented. Hyperacusis was reported in 73.5% of participants with SMS compared with 12.5% of unaffected siblings. This study offers the most comprehensive characterization of the auditory phenotype of SMS to date. The auditory profile in SMS is multifaceted and can include a previously unreported manifestation of hyperacusis. Routine audiologic surveillance is recommended as part of standard clinical care.

  2. Auditory Phenotype of Smith–Magenis Syndrome

    PubMed Central

    Brendal, Megan A.; King, Kelly A.; Zalewski, Christopher K.; Finucane, Brenda M.; Introne, Wendy; Smith, Ann C. M.

    2017-01-01

    Purpose The purpose of this study was to describe the auditory phenotype of a large cohort with Smith–Magenis syndrome (SMS), a rare disorder including physical anomalies, cognitive deficits, sleep disturbances, and a distinct behavioral phenotype. Method Hearing-related data were collected for 133 individuals with SMS aged 1–49 years. Audiogram data (97 participants) were used for cross-sectional and longitudinal analyses. Caregivers completed a sound sensitivity survey for 98 individuals with SMS and a control group of 24 unaffected siblings. Results Nearly 80% of participants with interpretable audiograms (n = 76) had hearing loss, which was typically slight to mild in degree. When hearing loss type could be determined (40 participants), sensorineural hearing loss (48.1%) occurred most often in participants aged 11–49 years. Conductive hearing loss (35.2%) was typically observed in children aged 1–10 years. A pattern of fluctuating and progressive hearing decline was documented. Hyperacusis was reported in 73.5% of participants with SMS compared with 12.5% of unaffected siblings. Conclusions This study offers the most comprehensive characterization of the auditory phenotype of SMS to date. The auditory profile in SMS is multifaceted and can include a previously unreported manifestation of hyperacusis. Routine audiologic surveillance is recommended as part of standard clinical care. PMID:28384694

  3. AgeFactDB--the JenAge Ageing Factor Database--towards data integration in ageing research.

    PubMed

    Hühne, Rolf; Thalheim, Torsten; Sühnel, Jürgen

    2014-01-01

    AgeFactDB (http://agefactdb.jenage.de) is a database aimed at the collection and integration of ageing phenotype data including lifespan information. Ageing factors are considered to be genes, chemical compounds or other factors such as dietary restriction, whose action results in a changed lifespan or another ageing phenotype. Any information related to the effects of ageing factors is called an observation and is presented on observation pages. To provide concise access to the complete information for a particular ageing factor, corresponding observations are also summarized on ageing factor pages. In a first step, ageing-related data were primarily taken from existing databases such as the Ageing Gene Database--GenAge, the Lifespan Observations Database and the Dietary Restriction Gene Database--GenDR. In addition, we have started to include new ageing-related information. Based on homology data taken from the HomoloGene Database, AgeFactDB also provides observation and ageing factor pages of genes that are homologous to known ageing-related genes. These homologues are considered as candidate or putative ageing-related genes. AgeFactDB offers a variety of search and browse options, and also allows the download of ageing factor or observation lists in TSV, CSV and XML formats.

  4. AgeFactDB—the JenAge Ageing Factor Database—towards data integration in ageing research

    PubMed Central

    Hühne, Rolf; Thalheim, Torsten; Sühnel, Jürgen

    2014-01-01

    AgeFactDB (http://agefactdb.jenage.de) is a database aimed at the collection and integration of ageing phenotype data including lifespan information. Ageing factors are considered to be genes, chemical compounds or other factors such as dietary restriction, whose action results in a changed lifespan or another ageing phenotype. Any information related to the effects of ageing factors is called an observation and is presented on observation pages. To provide concise access to the complete information for a particular ageing factor, corresponding observations are also summarized on ageing factor pages. In a first step, ageing-related data were primarily taken from existing databases such as the Ageing Gene Database—GenAge, the Lifespan Observations Database and the Dietary Restriction Gene Database—GenDR. In addition, we have started to include new ageing-related information. Based on homology data taken from the HomoloGene Database, AgeFactDB also provides observation and ageing factor pages of genes that are homologous to known ageing-related genes. These homologues are considered as candidate or putative ageing-related genes. AgeFactDB offers a variety of search and browse options, and also allows the download of ageing factor or observation lists in TSV, CSV and XML formats. PMID:24217911

  5. Asynchrony of senescence among phenotypic traits in a wild mammal population

    PubMed Central

    Hayward, Adam D.; Moorad, Jacob; Regan, Charlotte E.; Berenos, Camillo; Pilkington, Jill G.; Pemberton, Josephine M.; Nussey, Daniel H.

    2015-01-01

    The degree to which changes in lifespan are coupled to changes in senescence in different physiological systems and phenotypic traits is a central question in biogerontology. It is underpinned by deeper biological questions about whether or not senescence is a synchronised process, or whether levels of synchrony depend on species or environmental context. Understanding how natural selection shapes patterns of synchrony in senescence across physiological systems and phenotypic traits demands the longitudinal study of many phenotypes under natural conditions. Here, we examine the patterns of age-related variation in late adulthood in a wild population of Soay sheep (Ovis aries) that have been the subject of individual-based monitoring for thirty years. We examined twenty different phenotypic traits in both males and females, encompassing vital rates (survival and fecundity), maternal reproductive performance (offspring birth weight, birth date and survival), male rutting behaviour, home range measures, parasite burdens, and body mass. We initially quantified age-related variation in each trait having controlled for annual variation in the environment, among-individual variation and selective disappearance effects. We then standardised our age-specific trait means and tested whether age trajectories could be meaningfully grouped according to sex or the type of trait. Whilst most traits showed age-related declines in later life, we found striking levels of asynchrony both within and between the sexes. Of particular note, female fecundity and reproductive performance declined with age, but male annual reproductive success did not. We also discovered that whilst home range size and quality decline with age in females, home range size increases with age in males. Our findings highlight the complexity of phenotypic ageing under natural conditions and, along with emerging data from other wild populations and laboratory models, suggest that the long-standing hypothesis

  6. Variable phenotypic expression and onset in MYH14 distal hereditary motor neuropathy phenotype in a large, multigenerational North American family.

    PubMed

    Iyadurai, Stanley; Arnold, W David; Kissel, John T; Ruhno, Corey; Mcgovern, Vicki L; Snyder, Pamela J; Prior, Thomas W; Roggenbuck, Jennifer; Burghes, Arthur H; Kolb, Stephen J

    2017-08-01

    Distal hereditary motor neuropathy (dHMN) causes distal-predominant weakness without prominent sensory loss. Myosin heavy chain disorders most commonly result in distal myopathy and cardiomyopathy with or without hearing loss, but a complex phenotype with dHMN, myopathy, hoarseness, and hearing loss was reported in a Korean family with a c.2822G>T mutation in MYH14. In this study we report phenotypic features in a North American family with the c.2822G>T in MYH14. Clinical and molecular characterization was performed in a large, 6-generation, Caucasian family with MYH14 dHMN. A total of 11 affected and 7 unaffected individuals were evaluated and showed varying age of onset and severity of weakness. Genotypic concordance was confirmed with molecular analysis. Electrophysiological studies demonstrated distal motor axonal degeneration without myopathy in all affected subjects tested. Mutation of MYH14 can result in a range of neuromuscular phenotypes that includes a dHMN and hearing loss phenotype with variable age of onset. Muscle Nerve 56: 341-345, 2017. © 2016 Wiley Periodicals, Inc.

  7. Accelerated Aging of the M119 Simulator

    NASA Technical Reports Server (NTRS)

    Bixon, Eric R.

    2000-01-01

    This paper addresses the storage requirement, shelf life, and the reliability of M119 Whistling Simulator. Experimental conditions have been determined and the data analysis has been completed for the accelerated testing of the system. A general methodology to evaluate the shelf life of the system as a function of the storage time, temperature, and relative humidity is discussed.

  8. Impact of laboratory treatment with coloring and fluorescent liquids on the optical properties of zirconia before and after accelerated aging.

    PubMed

    Rafael, Caroline Freitas; Cesar, Paulo Francisco; Fredel, Marcio; Magini, Ricardo de Souza; Liebermann, Anja; Maziero Volpato, Cláudia Angela

    2018-03-15

    Laboratory procedures, such as dipping in coloring and fluorescent liquids, can be used to improve the optical properties of zirconia. However, information is lacking on the effect of these liquids. The purpose of this in vitro study was to evaluate the color differences and degree of fluorescence of zirconia (3Y-TZP) treated with coloring and fluorescent liquids before and after an accelerated aging protocol. Forty disk-shaped specimens of 3Y-TZP were fabricated by milling and separated according to the laboratory treatment performed: white zirconia (control group); zirconia treated with coloring liquid (A2 group); zirconia treated with fluorescent liquid (fluorescent group); and zirconia treated with both liquids (A2 fluorescent group). The L*a*b* coordinates before aging (T 0 ) were obtained with a spectrophotometer, and the degree of fluorescence was measured. The disks were subjected to accelerated aging for 1 hour (T 1 ) and 5 hours (T 2 ). Measurements were made before and after each time interval. Color differences (ΔE 00 ) were calculated using the CIEDE2000 formula and analyzed by 2-way ANOVA. Lightness (ΔL'), chroma (ΔC'), and hue differences (ΔH') were analyzed by multivariate ANOVA. Degrees of fluorescence were obtained as percentages and were analyzed by 2-way ANOVA. Multiple comparisons were performed by the Tukey HSD test (α=.05). Color differences were observed when 3Y-TZP disks were treated with coloring (7.91 ΔE 00 ), with fluorescent liquid (5.81 ΔE 00 ), and with both liquids (5.52 ΔE 00 ). Accelerated aging resulted in color differences in the T 2 A2 group (6.74 ΔE 00 ) and at both times evaluated in the fluorescent group (T 1 =8.59 ΔE 00 and T 2 =8.47 ΔE 00 ) (P<.001). In the A2 fluorescent group, the degree of fluorescence was not influenced significantly (P>.05). The use of fluorescent liquid influenced the degree of fluorescence in the fluorescent group (T 0 =20%). Significant differences in color, lightness, chroma, and hue

  9. Color change of composite resins subjected to accelerated artificial aging.

    PubMed

    Tornavoi, Denise Cremonezzi; Agnelli, José Augusto Marcondes; Panzeri, Heitor; Dos Reis, Andréa Cândido

    2013-01-01

    The aim of this study was to evaluate the influence of accelerated artificial aging (AAA) on the color change of composite resins used in dentistry. Three composite resins were evaluated: Two microhybrids and one hybrid of higher viscosity, with different amounts and sizes of filler particles, shades C2 and B2. A total of 54 specimens were obtained (18 for each composite resin), made of a Teflon matrix (15 mm in diameter and 2 mm in height). The color measurements were obtained with a Spectrophotometer, (PCB 6807 BYK Gardner) before and after AAA. Data were submitted to the Kolmogorov-Smirnov test (α >0.05), ANOVA and Tukey test (α <0.05). After statistical analysis, the color difference among composite resins with the same shades was analyzed. All composite resins showed unacceptable color changes after AAA (ΔE > 3). Considering the variable ∆E, it was observed that the color tone C2 was already statistically different for the microhybrid composite resin prior to AAA (P < 0.05) and in shade B2 for hybrid of higher viscosity and microhybrid with barium glass fluoride aluminum and silica dioxide (P < 0.01). After this process, a statistically significant difference was observed only for shade B2 between microhybrid composite resins (P < 0.01) and for hybrid of higher viscosity and microhybrid with barium glass fluoride aluminum and silica dioxide (P < 0.05). Regarding the color difference within a same composite resin group, before aging the composite resin hybrid of higher viscosity B2 showed the highest color variation rate and microhybrid with zirconium/silica C2 showed the lowest. All composite resins presented unacceptable color changes after 382 h of aging and different composite resins with same hue, presented different colors before being subjected to the aging process (B2 and C2) and after (B2). It was also observed color difference within a group of the same composite resin and same hue.

  10. Glutamate Cysteine Ligase Modifier Subunit (Gclm) Null Mice Have Increased Ovarian Oxidative Stress and Accelerated Age-Related Ovarian Failure

    PubMed Central

    Lim, Jinhwan; Nakamura, Brooke N.; Mohar, Isaac; Kavanagh, Terrance J.

    2015-01-01

    Glutathione (GSH) is the one of the most abundant intracellular antioxidants. Mice lacking the modifier subunit of glutamate cysteine ligase (Gclm), the rate-limiting enzyme in GSH synthesis, have decreased GSH. Our prior work showed that GSH plays antiapoptotic roles in ovarian follicles. We hypothesized that Gclm−/− mice have accelerated ovarian aging due to ovarian oxidative stress. We found significantly decreased ovarian GSH concentrations and oxidized GSH/oxidized glutathione redox potential in Gclm−/− vs Gclm+/+ ovaries. Prepubertal Gclm−/− and Gclm+/+ mice had similar numbers of ovarian follicles, and as expected, the total number of ovarian follicles declined with age in both genotypes. However, the rate of decline in follicles was significantly more rapid in Gclm−/− mice, and this was driven by accelerated declines in primordial follicles, which constitute the ovarian reserve. We found significantly increased 4-hydroxynonenal immunostaining (oxidative lipid damage marker) and significantly increased nitrotyrosine immunostaining (oxidative protein damage marker) in prepubertal and adult Gclm−/− ovaries compared with controls. The percentage of small ovarian follicles with increased granulosa cell proliferation was significantly higher in prepubertal and 2-month-old Gclm−/− vs Gclm+/+ ovaries, indicating accelerated recruitment of primordial follicles into the growing pool. The percentages of growing follicles with apoptotic granulosa cells were increased in young adult ovaries. Our results demonstrate increased ovarian oxidative stress and oxidative damage in young Gclm−/− mice, associated with an accelerated decline in ovarian follicles that appears to be mediated by increased recruitment of follicles into the growing pool, followed by apoptosis at later stages of follicular development. PMID:26083875

  11. The influence of aging and estradiol to progesterone ratio on rat macrophage phenotypic profile and NO and TNF-α production.

    PubMed

    Dimitrijević, Mirjana; Stanojević, Stanislava; Kuštrimović, Nataša; Mitić, Katarina; Vujić, Vesna; Aleksić, Iva; Radojević, Katarina; Leposavić, Gordana

    2013-11-01

    The phenotype and function of tissue macrophages substantially depend on the cellular milieu and biological effector molecules, such as steroid hormones, to which they are exposed. Furthermore, in female rats, aging is associated with the altered macrophage functioning and the increased estrogen level is followed by a decrease in that of progesterone. Therefore, the present study aimed to investigate the influence of estradiol/progesterone balance on rat macrophage function and phenotype throughout whole adult lifespan. We ovariectomized rats at the late prepubertal age or at the very end of reproductive lifespan, and examined the expression of ED2 (CD163, a marker of mature resident macrophages related to secretion of inflammatory mediators) on peritoneal macrophages and their ability to produce TNF-α and NO upon LPS-stimulation at different age points. In addition, to delineate direct and indirect effects of estrogen, we assessed the in vitro influence of different concentrations of 17β-estradiol on LPS-induced macrophage TNF-α and NO production. Results showed that: (a) the low frequency of ED2(high) cells amongst peritoneal macrophages of aged rats was accompanied with the reduced TNF-α, but not NO production; (b) estradiol level gradually increased following ovariectomy; (c) macrophage ED2 expression and TNF-α production were dependent on estradiol/progesterone balance and they changed in the same direction; (d) changes in estradiol/progesterone balance differentially affected macrophages TNF-α and NO production; and (e) estradiol exerted pro-inflammatory and anti-inflammatory effects on macrophages in vivo and in vitro, respectively. Overall, our study discloses that estradiol/progesterone balance contributes to the fine-tuning of rat macrophage secretory capacity, and adds to a better understanding of the ovarian steroid hormone role in the regulation of macrophage function, and its significance for the age-associated changes in innate immunity.

  12. Fanconi Anemia: A DNA repair disorder characterized by accelerated decline of the hematopoietic stem cell compartment and other features of aging.

    PubMed

    Brosh, Robert M; Bellani, Marina; Liu, Yie; Seidman, Michael M

    2017-01-01

    Fanconi Anemia (FA) is a rare autosomal genetic disorder characterized by progressive bone marrow failure (BMF), endocrine dysfunction, cancer, and other clinical features commonly associated with normal aging. The anemia stems directly from an accelerated decline of the hematopoietic stem cell compartment. Although FA is a complex heterogeneous disease linked to mutations in 19 currently identified genes, there has been much progress in understanding the molecular pathology involved. FA is broadly considered a DNA repair disorder and the FA gene products, together with other DNA repair factors, have been implicated in interstrand cross-link (ICL) repair. However, in addition to the defective DNA damage response, altered epigenetic regulation, and telomere defects, FA is also marked by elevated levels of inflammatory mediators in circulation, a hallmark of faster decline in not only other hereditary aging disorders but also normal aging. In this review, we offer a perspective of FA as a monogenic accelerated aging disorder, citing the latest evidence for its multi-factorial deficiencies underlying its unique clinical and cellular features. Published by Elsevier B.V.

  13. The senescence accelerated mouse prone 8 (SAMP8): A novel murine model for cardiac aging.

    PubMed

    Karuppagounder, Vengadeshprabhu; Arumugam, Somasundaram; Babu, Sahana Suresh; Palaniyandi, Suresh S; Watanabe, Kenichi; Cooke, John P; Thandavarayan, Rajarajan A

    2017-05-01

    Because cardiovascular disease remains the major cause of mortality and morbidity world-wide, there remains a compelling need for new insights and novel therapeutic avenues. In this regard, the senescence-accelerated mouse prone 8 (SAMP8) line is a particularly good model for studying the effects of aging on cardiovascular health. Accumulating evidence suggests that this model may shed light on age-associated cardiac and vascular dysfunction and disease. These animals manifest evidence of inflammation, oxidative stress and adverse cardiac remodeling that may recapitulate processes involved in human disease. Early alterations in oxidative damage promote endoplasmic reticulum stress to trigger apoptosis and cytokine production in this genetically susceptible mouse strain. Conversely, pharmacological treatments that reduce inflammation and oxidative stress improve cardiac function in these animals. Therefore, the SAMP8 mouse model provides an exciting opportunity to expand our knowledge of aging in cardiovascular disease and the potential identification of novel targets of treatment. Herein, we review the previous studies performed in SAMP8 mice that provide insight into age-related cardiovascular alterations. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Holocene age of the Yuha burial: Direct radiocarbon determinations by accelerator mass spectrometry

    USGS Publications Warehouse

    Stafford, Thomas W.; Jull, A.J.T.; Zabel, T.H.; Donahue, D.J.; Duhamel, R.C.; Brendel, K.; Haynes, C.V.; Bischoff, J.L.; Payen, L.A.; Taylor, R.E.

    1984-01-01

    The view that human populations may not have arrived in the Western Hemisphere before about 12,000 radiocarbon yr BP1,2 has been challenged by claims of much greater antiquity for a small number of archaeological sites and human skeleton samples. One such site is the Homo sapiens sapiens cairn burial excavated in 1971 from the Yuha desert, Imperial County, California3-5. Radiocarbon analysis of caliche coating one of the bones of the skeleton yielded a radiocarbon age of 21,500??1,000 yr BP4, while radiocarbon and uranium series analyses of caliche coating a cairn boulder yielded ages of 22,125??400 and 19,000??3,000 yr BP, respectively5. The late Pleistocene age assignment to the Yuha burial has been challenged by comparing the cultural context of the burial with other cairn burials in the same region6, on the basis of the site's geomorphological context and from radiocarbon analyses of soil caliches. 7,8 In rebuttal, arguments in defence of the original age assignment have been presented9,10 as well as an amino acid racemization analysis on the Yuha skeleton indicating an age of 23,600??2,600 yr BP11. The tandem accelerator mass spectrometer at the University of Arizona has now been used to measure the ratio of 14C/13C in several organic and inorganic fractions of post-cranial bone from the Yuha H. sapiens sapiens skeleton. Isotope ratios from six chemical fractions all yielded radiocarbon ages for the skeleton of less than 4,000 yr BP. These results indicate that the Yuha skeleton is of Holocene age, in agreement with the cultural context of the burial, and in disagreement with the previously assigned Pleistocene age of 19,000-23,000 yr. ?? 1984 Nature Publishing Group.

  15. The influence of the accelerated ageing on the black screen element of the Electroink prints

    NASA Astrophysics Data System (ADS)

    Majnaric, I.; Bolanca, Z.; Bolanca Mirkovic, I.

    2010-06-01

    Printing material and prints undergo changes during ageing which can be recognized in deterioration in the physical, chemical and optical properties. The aim of this work is to determine the optical changes of the prints caused by ageing of the printing material and of the prints obtained by the application of the indirect electrophotography. The change of the screen elements in lighter halftone areas, which was obtained by the usage of the microscopic image analysis, has been discussed in the article. For the preparation of samples the following papers were used: fine art paper, recycled paper and offset paper as well as black Electroink. Three sample series were observed: prints on nonaged paper and ElectroInk, prints on aged paper and ElectroInk and prints on aged paper and nonaged ElectroInk. The investigation results show that by ageing of the uncoated printing substrates the decrease of the dots on prints can be expected, while the printing on the aged paper results in the increased reproduction of the halftone dots. The obtained results are the contribution to the explanation of the influence of the accelerated ageing process of papers which are used for printing and the aged prints on the halftone dot changes. Except the mentioned determined scientific contribution the results are applicable in the area of the printing product quality as well as in the forensic science.

  16. Phenotypic and Gene Expression Modification with Normal Brain Aging in GFAP-Positive Astrocytes and Neural Stem Cells

    PubMed Central

    Bernal, Giovanna M.; Peterson, Daniel A.

    2011-01-01

    Summary Astrocytes secrete growth factors that are both neuroprotective and supportive for the local environment. Identified by glial fibrillary acidic protein (GFAP) expression, astrocytes exhibit heterogeneity in morphology and in expression of phenotypic markers and growth factors throughout different adult brain regions. In adult neurogenic niches, astrocytes secrete vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) within the neurogenic niche, and are also a source of special GFAP-positive multipotent neural stem cells (NSCs). Normal aging is accompanied by a decline in CNS function and reduced neurogenesis. We asked if a decreased availability of astrocyte-derived factors may contribute to the age-related decline in neurogenesis. Determining alterations of astrocytic activity in the aging brain is crucial for understanding CNS homeostasis in aging and for assessing appropriate therapeutic targets for an aging population. We found region-specific alterations in gene expression of GFAP, VEGF and FGF-2 and their receptors in the aged brain corresponding to changes in astrocytic reactivity, supporting astrocytic heterogeneity and demonstrating a differential aging effect. We found that GFAP-positive NSCs uniquely coexpress both VEGF and its key mitotic receptor Flk-1 in both young and aged hippocampus, indicating a possible autocrine/paracrine signaling mechanism. VEGF expression is lost once NSCs commit to a neuronal fate, but Flk-1-mediated sensitivity to VEGF signaling is maintained. We propose that age-related astrocytic changes result in reduced VEGF and FGF-2 signaling, which in turn limits neural stem cell and progenitor cell maintenance and contributes to decreased neurogenesis. PMID:21385309

  17. Stepwise Distributed Open Innovation Contests for Software Development: Acceleration of Genome-Wide Association Analysis.

    PubMed

    Hill, Andrew; Loh, Po-Ru; Bharadwaj, Ragu B; Pons, Pascal; Shang, Jingbo; Guinan, Eva; Lakhani, Karim; Kilty, Iain; Jelinsky, Scott A

    2017-05-01

    The association of differing genotypes with disease-related phenotypic traits offers great potential to both help identify new therapeutic targets and support stratification of patients who would gain the greatest benefit from specific drug classes. Development of low-cost genotyping and sequencing has made collecting large-scale genotyping data routine in population and therapeutic intervention studies. In addition, a range of new technologies is being used to capture numerous new and complex phenotypic descriptors. As a result, genotype and phenotype datasets have grown exponentially. Genome-wide association studies associate genotypes and phenotypes using methods such as logistic regression. As existing tools for association analysis limit the efficiency by which value can be extracted from increasing volumes of data, there is a pressing need for new software tools that can accelerate association analyses on large genotype-phenotype datasets. Using open innovation (OI) and contest-based crowdsourcing, the logistic regression analysis in a leading, community-standard genetics software package (PLINK 1.07) was substantially accelerated. OI allowed us to do this in <6 months by providing rapid access to highly skilled programmers with specialized, difficult-to-find skill sets. Through a crowd-based contest a combination of computational, numeric, and algorithmic approaches was identified that accelerated the logistic regression in PLINK 1.07 by 18- to 45-fold. Combining contest-derived logistic regression code with coarse-grained parallelization, multithreading, and associated changes to data initialization code further developed through distributed innovation, we achieved an end-to-end speedup of 591-fold for a data set size of 6678 subjects by 645 863 variants, compared to PLINK 1.07's logistic regression. This represents a reduction in run time from 4.8 hours to 29 seconds. Accelerated logistic regression code developed in this project has been incorporated

  18. Genotype-phenotype associations in obesity dependent on definition of the obesity phenotype.

    PubMed

    Kring, Sofia Inez Iqbal; Larsen, Lesli Hingstrup; Holst, Claus; Toubro, Søren; Hansen, Torben; Astrup, Arne; Pedersen, Oluf; Sørensen, Thorkild I A

    2008-01-01

    In previous studies of associations of variants in the genes UCP2, UCP3, PPARG2, CART, GRL, MC4R, MKKS, SHP, GHRL, and MCHR1 with obesity, we have used a case-control approach with cases defined by a threshold for BMI. In the present study, we assess the association of seven abdominal, peripheral, and overall obesity phenotypes, which were analyzed quantitatively, and thirteen candidate gene polymorphisms in these ten genes in the same cohort. Obese Caucasian men (n = 234, BMI >or= 31.0 kg/m(2)) and a randomly sampled non-obese group (n = 323), originally identified at the draft board examinations, were re-examined at median ages of 47.0 or 49.0 years by anthropometry and DEXA scanning. Obesity phenotypes included BMI, fat body mass index, waist circumference, waist for given BMI, intra-abdominal adipose tissue, hip circumference and lower body fat mass (%). Using logistic regression models, we estimated the odds for defined genotypes (dominant or recessive genetic transmission) in relation to z-scores of the phenotypes. The minor (rare) allele for SHP 512G>C (rs6659176) was associated with increased hip circumference. The minor allele for UCP2 Ins45bp was associated with increased BMI, increased abdominal obesity, and increased hip circumference. The minor allele for UCP2 -866G>A (rs6593669) was associated with borderline increased fat body mass index. The minor allele for MCHR1 100213G>A (rs133072) was associated with reduced abdominal obesity. None of the other genotype-phenotype combinations showed appreciable associations. If replicated in independent studies with focus on the specific phenotypes, our explorative studies suggest significant associations between some candidate gene polymorphisms and distinct obesity phenotypes, predicting beneficial and detrimental effects, depending on compartments for body fat accumulation. Copyright 2008 S. Karger AG, Basel.

  19. Heritability of and mortality prediction with a longevity phenotype: the healthy aging index.

    PubMed

    Sanders, Jason L; Minster, Ryan L; Barmada, M Michael; Matteini, Amy M; Boudreau, Robert M; Christensen, Kaare; Mayeux, Richard; Borecki, Ingrid B; Zhang, Qunyuan; Perls, Thomas; Newman, Anne B

    2014-04-01

    Longevity-associated genes may modulate risk for age-related diseases and survival. The Healthy Aging Index (HAI) may be a subphenotype of longevity, which can be constructed in many studies for genetic analysis. We investigated the HAI's association with survival in the Cardiovascular Health Study and heritability in the Long Life Family Study. The HAI includes systolic blood pressure, pulmonary vital capacity, creatinine, fasting glucose, and Modified Mini-Mental Status Examination score, each scored 0, 1, or 2 using approximate tertiles and summed from 0 (healthy) to 10 (unhealthy). In Cardiovascular Health Study, the association with mortality and accuracy predicting death were determined with Cox proportional hazards analysis and c-statistics, respectively. In Long Life Family Study, heritability was determined with a variance component-based family analysis using a polygenic model. Cardiovascular Health Study participants with unhealthier index scores (7-10) had 2.62-fold (95% confidence interval: 2.22, 3.10) greater mortality than participants with healthier scores (0-2). The HAI alone predicted death moderately well (c-statistic = 0.643, 95% confidence interval: 0.626, 0.661, p < .0001) and slightly worse than age alone (c-statistic = 0.700, 95% confidence interval: 0.684, 0.717, p < .0001; p < .0001 for comparison of c-statistics). Prediction increased significantly with adjustment for demographics, health behaviors, and clinical comorbidities (c-statistic = 0.780, 95% confidence interval: 0.765, 0.794, p < .0001). In Long Life Family Study, the heritability of the HAI was 0.295 (p < .0001) overall, 0.387 (p < .0001) in probands, and 0.238 (p = .0004) in offspring. The HAI should be investigated further as a candidate phenotype for uncovering longevity-associated genes in humans.

  20. Accelerated Changes in Cortical Thickness Measurements with Age in Military Service Members with Traumatic Brain Injury.

    PubMed

    Savjani, Ricky R; Taylor, Brian A; Acion, Laura; Wilde, Elisabeth A; Jorge, Ricardo E

    2017-11-15

    Finding objective and quantifiable imaging markers of mild traumatic brain injury (TBI) has proven challenging, especially in the military population. Changes in cortical thickness after injury have been reported in animals and in humans, but it is unclear how these alterations manifest in the chronic phase, and it is difficult to characterize accurately with imaging. We used cortical thickness measures derived from Advanced Normalization Tools (ANTs) to predict a continuous demographic variable: age. We trained four different regression models (linear regression, support vector regression, Gaussian process regression, and random forests) to predict age from healthy control brains from publicly available datasets (n = 762). We then used these models to predict brain age in military Service Members with TBI (n = 92) and military Service Members without TBI (n = 34). Our results show that all four models overpredicted age in Service Members with TBI, and the predicted age difference was significantly greater compared with military controls. These data extend previous civilian findings and show that cortical thickness measures may reveal an association of accelerated changes over time with military TBI.

  1. Natural History of Aging in Cornelia de Lange Syndrome

    PubMed Central

    KLINE, ANTONIE D.; GRADOS, MARCO; SPONSELLER, PAUL; LEVY, HOWARD P.; BLAGOWIDOW, NATALIE; SCHOEDEL, CHRISTIANNE; RAMPOLLA, JONI; CLEMENS, DOUGLAS K.; KRANTZ, IAN; KIMBALL, AMY; PICHARD, CARMEN; TUCHMAN, DAVID

    2016-01-01

    Observations about the natural history of aging in Cornelia de Lange syndrome (CdLS) are made, based on 49 patients from a multidisciplinary clinic for adolescents and adults. The mean age was 17 years. Although most patients remain small, obesity may develop. Gastroesophageal reflux persists or worsens, and there are early long-term sequelae, including Barrett esophagus in 10%; other gastrointestinal findings include risk for volvulus, rumination, and chronic constipation. Submucous cleft palate was found in 14%, most undetected before our evaluation. Chronic sinusitis was noted in 39%, often with nasal polyps. Blepharitis improves with age; cataracts and detached retina may occur. Decreased bone density is observed, with occasional fractures. One quarter have leg length discrepancy and 39% scoliosis. Most females have delayed or irregular menses but normal gynecologic exams and pap smears. Benign prostatic hypertrophy occurred in one male prior to 40 years. The phenotype is variable, but there is a distinct pattern of facial changes with aging. Premature gray hair is frequent; two patients had cutis verticis gyrata. Behavioral issues and specific psychiatric diagnoses, including self-injury, anxiety, attention-deficit disorder, autistic features, depression, and obsessive-compulsive behavior, often worsen with age. This work presents some evidence for accelerated aging in CdLS. Of 53% with mutation analysis, 55% demonstrate a detectable mutation in NIPBL or SMC1A. Although no specific genotype–phenotype correlations have been firmly established, individuals with missense mutations in NIPBL and SMC1A appear milder than those with other mutations. Based on these observations, recommendations for clinical management of adults with CdLS are made. PMID:17640042

  2. A roadmap for the genetic analysis of renal aging

    PubMed Central

    Noordmans, Gerda A; Hillebrands, Jan-Luuk; van Goor, Harry; Korstanje, Ron

    2015-01-01

    Several studies show evidence for the genetic basis of renal disease, which renders some individuals more prone than others to accelerated renal aging. Studying the genetics of renal aging can help us to identify genes involved in this process and to unravel the underlying pathways. First, this opinion article will give an overview of the phenotypes that can be observed in age-related kidney disease. Accurate phenotyping is essential in performing genetic analysis. For kidney aging, this could include both functional and structural changes. Subsequently, this article reviews the studies that report on candidate genes associated with renal aging in humans and mice. Several loci or candidate genes have been found associated with kidney disease, but identification of the specific genetic variants involved has proven to be difficult. CUBN, UMOD, and SHROOM3 were identified by human GWAS as being associated with albuminuria, kidney function, and chronic kidney disease (CKD). These are promising examples of genes that could be involved in renal aging, and were further mechanistically evaluated in animal models. Eventually, we will provide approaches for performing genetic analysis. We should leverage the power of mouse models, as testing in humans is limited. Mouse and other animal models can be used to explain the underlying biological mechanisms of genes and loci identified by human GWAS. Furthermore, mouse models can be used to identify genetic variants associated with age-associated histological changes, of which Far2, Wisp2, and Esrrg are examples. A new outbred mouse population with high genetic diversity will facilitate the identification of genes associated with renal aging by enabling high-resolution genetic mapping while also allowing the control of environmental factors, and by enabling access to renal tissues at specific time points for histology, proteomics, and gene expression. PMID:26219736

  3. Phenotypic and gene expression modification with normal brain aging in GFAP-positive astrocytes and neural stem cells.

    PubMed

    Bernal, Giovanna M; Peterson, Daniel A

    2011-06-01

    Astrocytes secrete growth factors that are both neuroprotective and supportive for the local environment. Identified by glial fibrillary acidic protein (GFAP) expression, astrocytes exhibit heterogeneity in morphology and in the expression of phenotypic markers and growth factors throughout different adult brain regions. In adult neurogenic niches, astrocytes secrete vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) within the neurogenic niche and are also a source of special GFAP-positive multipotent neural stem cells (NSCs). Normal aging is accompanied by a decline in CNS function and reduced neurogenesis. We asked whether a decreased availability of astrocyte-derived factors may contribute to the age-related decline in neurogenesis. Determining alterations of astrocytic activity in the aging brain is crucial for understanding CNS homeostasis in aging and for assessing appropriate therapeutic targets for an aging population. We found region-specific alterations in the gene expression of GFAP, VEGF, and FGF-2 and their receptors in the aged brain corresponding to changes in astrocytic reactivity, supporting astrocytic heterogeneity and demonstrating a differential aging effect. We found that GFAP-positive NSCs uniquely coexpress both VEGF and its key mitotic receptor Flk-1 in both young and aged hippocampus, indicating a possible autocrine/paracrine signaling mechanism. VEGF expression is lost once NSCs commit to a neuronal fate, but Flk-1-mediated sensitivity to VEGF signaling is maintained. We propose that age-related astrocytic changes result in reduced VEGF and FGF-2 signaling, which in turn limits NSC and progenitor cell maintenance and contributes to decreased neurogenesis. © 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

  4. Geographic atrophy phenotype identification by cluster analysis.

    PubMed

    Monés, Jordi; Biarnés, Marc

    2018-03-01

    To identify ocular phenotypes in patients with geographic atrophy secondary to age-related macular degeneration (GA) using a data-driven cluster analysis. This was a retrospective analysis of data from a prospective, natural history study of patients with GA who were followed for ≥6 months. Cluster analysis was used to identify subgroups within the population based on the presence of several phenotypic features: soft drusen, reticular pseudodrusen (RPD), primary foveal atrophy, increased fundus autofluorescence (FAF), greyish FAF appearance and subfoveal choroidal thickness (SFCT). A comparison of features between the subgroups was conducted, and a qualitative description of the new phenotypes was proposed. The atrophy growth rate between phenotypes was then compared. Data were analysed from 77 eyes of 77 patients with GA. Cluster analysis identified three groups: phenotype 1 was characterised by high soft drusen load, foveal atrophy and slow growth; phenotype 3 showed high RPD load, extrafoveal and greyish FAF appearance and thin SFCT; the characteristics of phenotype 2 were midway between phenotypes 1 and 3. Phenotypes differed in all measured features (p≤0.013), with decreases in the presence of soft drusen, foveal atrophy and SFCT seen from phenotypes 1 to 3 and corresponding increases in high RPD load, high FAF and greyish FAF appearance. Atrophy growth rate differed between phenotypes 1, 2 and 3 (0.63, 1.91 and 1.73 mm 2 /year, respectively, p=0.0005). Cluster analysis identified three distinct phenotypes in GA. One of them showed a particularly slow growth pattern. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  5. The electrical performance of polymeric insulating materials under accelerated aging in a fog chamber

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gorur, R.S.; Cherney, E.A.; Hackam, R.

    1988-07-01

    A comparative study of the ac (60 Hz) surface aging in a fog chamber is reported on cylindrical rod samples of high temperature vulcanized (HTV) silicone rubber and ethylene propylene diene monomer (EPDM) rubber containing various amounts of alumina trihydrate (ATH) and/or silica fillers. In low conductivity (250 ..mu..S/cm) fog, silicone rubber performed better than EPDM samples whereas in high conductivity (1000 ..mu..S/cm) fog, the order of performance was reversed. The mechanisms by which fillers impart tracking and erosion resistance to materials is discussed as influenced by the experimental conditions of the accelerated aging tests. Surface studies by ESCA (Electronmore » Spectroscopy for Chemical Analysis) demonstrate that the hydrophobicity of silicone rubber, despite the accumulation of surface contamination, can be attributed to migration of low molecular weight polymer chains and/or mobile fluids, such as silicone oil.« less

  6. Prevention of age-related macular degeneration-like retinopathy by rapamycin in rats.

    PubMed

    Kolosova, Nataliya G; Muraleva, Natalia A; Zhdankina, Anna A; Stefanova, Natalia A; Fursova, Anzhela Z; Blagosklonny, Mikhail V

    2012-08-01

    Age-related macular degeneration, a neurodegenerative and vascular retinal disease, is the most common cause of blindness in the Western countries. Evidence accumulates that target of rapamycin is involved in aging and age-related diseases, including neurodegeneration. The target of rapamycin inhibitor, rapamycin, suppresses the senescent cell phenotype and extends life span in diverse species, including mice. Rapamycin decreases senescence-associated phenotypes in retinal pigment epithelial cells in culture. Herein, we investigated the effect of rapamycin on spontaneous retinopathy in senescence-accelerated OXYS rats, an animal model of age-related macular degeneration. Rats were treated with either 0.1 or 0.5 mg/kg rapamycin, which was given orally as a food mixture. In a dose-dependent manner, rapamycin decreased the incidence and severity of retinopathy. Rapamycin improved some (but not all) histological abnormalities associated with retinopathy. Thus, in retinal pigment epithelial cell layers, rapamycin decreased nuclei heterogeneity and normalized intervals between nuclei. In photoreceptor cells, associated neurons, and radial glial cells, rapamycin prevented nuclear and cellular pyknosis. More important, rapamycin prevented destruction of ganglionar neurons in the retina. Rapamycin did not exert any adverse effects on the retina in control disease-free Wistar rats. Taken together, our data suggest the therapeutic potential of rapamycin for treatment and prevention of retinopathy. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  7. Metabolic syndrome but not obesity measures are risk factors for accelerated age-related glomerular filtration rate decline in the general population.

    PubMed

    Stefansson, Vidar T N; Schei, Jørgen; Solbu, Marit D; Jenssen, Trond G; Melsom, Toralf; Eriksen, Bjørn O

    2018-05-01

    Rapid age-related glomerular filtration rate (GFR) decline increases the risk of end-stage renal disease, and a low GFR increases the risk of mortality and cardiovascular disease. High body mass index and the metabolic syndrome are well-known risk factors for patients with advanced chronic kidney disease, but their role in accelerating age-related GFR decline independent of cardiovascular disease, hypertension and diabetes is not adequately understood. We studied body mass index, waist circumference, waist-hip ratio and metabolic syndrome as risk factors for accelerated GFR decline in 1261 middle-aged people representative of the general population without diabetes, cardiovascular disease or kidney disease. GFR was measured as iohexol clearance at baseline and repeated after a median of 5.6 years. Metabolic syndrome was defined as fulfilling three out of five criteria, based on waist circumference, blood pressure, glucose, high-density lipoprotein cholesterol and triglycerides. The mean GFR decline rate was 0.95 ml/min/year. Neither the body mass index, waist circumference nor waist-hip ratio predicted statistically significant changes in age-related GFR decline, but individuals with baseline metabolic syndrome had a significant mean of 0.30 ml/min/year faster decline than individuals without metabolic syndrome in a multivariable adjusted linear regression model. This association was mainly driven by the triglyceride criterion of metabolic syndrome, which was associated with a significant 0.36 ml/min/year faster decline when analyzed separately. Results differed significantly when GFR was estimated using creatinine and/or cystatin C. Thus, metabolic syndrome, but not the body mass index, waist circumference or waist-hip ratio, is an independent risk factor for accelerated age-related GFR decline in the general population. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  8. Brain enlargement is associated with regression in preschool-age boys with autism spectrum disorders

    PubMed Central

    Nordahl, Christine Wu; Lange, Nicholas; Li, Deana D.; Barnett, Lou Ann; Lee, Aaron; Buonocore, Michael H.; Simon, Tony J.; Rogers, Sally; Ozonoff, Sally; Amaral, David G.

    2011-01-01

    Autism is a heterogeneous disorder with multiple behavioral and biological phenotypes. Accelerated brain growth during early childhood is a well-established biological feature of autism. Onset pattern, i.e., early onset or regressive, is an intensely studied behavioral phenotype of autism. There is currently little known, however, about whether, or how, onset status maps onto the abnormal brain growth. We examined the relationship between total brain volume and onset status in a large sample of 2- to 4-y-old boys and girls with autism spectrum disorder (ASD) [n = 53, no regression (nREG); n = 61, regression (REG)] and a comparison group of age-matched typically developing controls (n = 66). We also examined retrospective head circumference measurements from birth through 18 mo of age. We found that abnormal brain enlargement was most commonly found in boys with regressive autism. Brain size in boys without regression did not differ from controls. Retrospective head circumference measurements indicate that head circumference in boys with regressive autism is normal at birth but diverges from the other groups around 4–6 mo of age. There were no differences in brain size in girls with autism (n = 22, ASD; n = 24, controls). These results suggest that there may be distinct neural phenotypes associated with different onsets of autism. For boys with regressive autism, divergence in brain size occurs well before loss of skills is commonly reported. Thus, rapid head growth may be a risk factor for regressive autism. PMID:22123952

  9. D-Galactose High-Dose Administration Failed to Induce Accelerated Aging Changes in Neurogenesis, Anxiety, and Spatial Memory on Young Male Wistar Rats.

    PubMed

    Cardoso, Armando; Magano, Sara; Marrana, Francisco; Andrade, José P

    2015-12-01

    The model of accelerated senescence with the prolonged administration of d-galactose is used in anti-aging studies because it mimics several aging-associated alterations such as increase of oxidative stress and decline of cognition. However, there is no standardized protocol for this aging model, and recently some reports have questioned its effectiveness. To clarify this issue, we used a model of high-dose d-galactose on 1-month-old male Wistar rats and studied the hippocampus, one of the most affected brain regions. In one group (n = 10), d-galactose was daily administered intraperitoneally (300 mg/kg) during 8 weeks whereas age-matched controls (n = 10) were injected intraperitoneally with saline. A third group (n = 10) was treated with the same dose of d-galactose and with oral epigallocatechin-3-gallate (EGCG) (2 grams/L), a green tea catechin with anti-oxidant and neuroprotective properties. After treatments, animals were submitted to open-field, elevated plus-maze and Morris water maze tests, and neurogenesis in the dentate gyrus subgranular layer was quantified. There were no significant alterations when the three groups were compared in the number of doublecortin- and Ki-67-immunoreactive cells, and also on anxiety levels, spatial learning, and memory. Therefore, d-galactose was not effective in the induction of accelerated aging, and EGCG administered to d-galactose-treated animals did not improve behavior and had no effects on neurogenesis. We conclude that daily 300 mg/kg of d-galactose administered intraperitoneally may not be a suitable model for inducing age-related neurobehavioral alterations in young male Wistar rats. More studies are necessary to obtain a reliable and reproducible model of accelerated senescence in rodents using d-galactose.

  10. Intrauterine growth restriction programs an accelerated age-related increase in cardiovascular risk in male offspring

    PubMed Central

    Dasinger, John Henry; Intapad, Suttira; Backstrom, Miles A.; Carter, Anthony J.

    2016-01-01

    Placental insufficiency programs an increase in blood pressure associated with a twofold increase in serum testosterone in male growth-restricted offspring at 4 mo of age. Population studies indicate that the inverse relationship between birth weight and blood pressure is amplified with age. Thus, we tested the hypothesis that intrauterine growth restriction programs an age-related increase in blood pressure in male offspring. Growth-restricted offspring retained a significantly higher blood pressure at 12 but not at 18 mo of age compared with age-matched controls. Blood pressure was significantly increased in control offspring at 18 mo of age relative to control counterparts at 12 mo; however, blood pressure was not increased in growth-restricted at 18 mo relative to growth-restricted counterparts at 12 mo. Serum testosterone levels were not elevated in growth-restricted offspring relative to control at 12 mo of age. Thus, male growth-restricted offspring no longer exhibited a positive association between blood pressure and testosterone at 12 mo of age. Unlike hypertension in male growth-restricted offspring at 4 mo of age, inhibition of the renin-angiotensin system with enalapril (250 mg/l for 2 wk) did not abolish the difference in blood pressure in growth-restricted offspring relative to control counterparts at 12 mo of age. Therefore, these data suggest that intrauterine growth restriction programs an accelerated age-related increase in blood pressure in growth-restricted offspring. Furthermore, this study suggests that the etiology of increased blood pressure in male growth-restricted offspring at 12 mo of age differs from that at 4 mo of age. PMID:27147668

  11. Evolution on neutral networks accelerates the ticking rate of the molecular clock

    PubMed Central

    Manrubia, Susanna; Cuesta, José A.

    2015-01-01

    Large sets of genotypes give rise to the same phenotype, because phenotypic expression is highly redundant. Accordingly, a population can accept mutations without altering its phenotype, as long as the genotype mutates into another one on the same set. By linking every pair of genotypes that are mutually accessible through mutation, genotypes organize themselves into neutral networks (NNs). These networks are known to be heterogeneous and assortative, and these properties affect the evolutionary dynamics of the population. By studying the dynamics of populations on NNs with arbitrary topology, we analyse the effect of assortativity, of NN (phenotype) fitness and of network size. We find that the probability that the population leaves the network is smaller the longer the time spent on it. This progressive ‘phenotypic entrapment’ entails a systematic increase in the overdispersion of the process with time and an acceleration in the fixation rate of neutral mutations. We also quantify the variation of these effects with the size of the phenotype and with its fitness relative to that of neighbouring alternatives. PMID:25392402

  12. [Autonomic regulation at emotional stress under hypoxic conditions in the elderly with physiological and accelerated aging: effect of hypoxic training].

    PubMed

    Os'mak, E D; Asanov, É O

    2014-01-01

    The effect of hypoxic training on autonomic regulation in psycho-emotional stress conditions in hypoxic conditions in older people with physiological (25 people) and accelerated (28 people) aging respiratory system. It is shown that hypoxic training leads to an increase in vagal activity indicators (HF) and reduced simpatovagal index (LF/HF), have a normalizing effect on the autonomic balance during stress loads in older people with different types of aging respiratory system.

  13. FRAILTY AND CONSTELLATIONS OF FACTORS IN AGING HIV-INFECTED AND UNINFECTED WOMEN - THE WOMEN'S INTERAGENCY HIV STUDY

    PubMed Central

    GUSTAFSON, D.R.; SHI, Q.; THURN, M.; HOLMAN, S.A.; MINKOFF, H.; COHEN, M.; PLANKEY, M.W.; HAVLIK, R.; SHARMA, A.; GANGE, S.; GANDHI, M.; MILAM, J.; HOOVER, D.

    2016-01-01

    Background Biological similarities are noted between aging and HIV infection. Middle-aged adults with HIV infection may present as elderly due to accelerated aging or having more severe aging phenotypes occurring at younger ages. Objectives We explored age-adjusted prevalence of frailty, a geriatric condition, among HIV+ and at risk HIV− women. Design Cross-sectional. Setting The Women's Interagency HIV Study (WIHS). Participants 2028 middle-aged (average age 39 years) female participants (1449 HIV+; 579 HIV−). Measurements The Fried Frailty Index (FFI), HIV status variables, and constellations of variables representing Demographic/health behaviors and Aging-related chronic diseases. Associations between the FFI and other variables were estimated, followed by stepwise regression models. Results Overall frailty prevalence was 15.2% (HIV+, 17%; HIV−, 10%). A multivariable model suggested that HIV infection with CD4 count<200; age>40 years; current or former smoking; income ≤$12,000; moderate vs low fibrinogen-4 (FIB-4) levels; and moderate vs high estimated glomerular filtration rate (eGFR) were positively associated with frailty. Low or moderate drinking was protective. Conclusions Frailty is a multidimensional aging phenotype observed in mid-life among women with HIV infection. Prevalence of frailty in this sample of HIV-infected women exceeds that for usual elderly populations. This highlights the need for geriatricians and gerontologists to interact with younger `at risk' populations, and assists in the formulation of best recommendations for frailty interventions to prevent early aging, excess morbidities and early death. PMID:26980368

  14. [Behavioural phenotypes in Prader-Willi syndrome].

    PubMed

    Rosell-Raga, L

    2003-02-01

    The behavioural phenotype of Prader-Willi syndrome (PWS) is defined by a neurological profile and a characteristic pattern of behavioural disorders which include cognitive deficits, learning difficulties and behavioural problems, which increase with age, both in number and gravity. We review the behavioural phenotype of the cases of PWS in the Valencian Community, together with their peculiar behaviours, and analyse how these generate family and social problems. The description of a peculiar behaviour opens up new horizons when understanding and treating PWS, both from a pharmacological and neuropsychological perspective.

  15. Accelerated life testing of spacecraft subsystems

    NASA Technical Reports Server (NTRS)

    Wiksten, D.; Swanson, J.

    1972-01-01

    The rationale and requirements for conducting accelerated life tests on electronic subsystems of spacecraft are presented. A method for applying data on the reliability and temperature sensitivity of the parts contained in a sybsystem to the selection of accelerated life test parameters is described. Additional considerations affecting the formulation of test requirements are identified, and practical limitations of accelerated aging are described.

  16. Mechanical and Chemical Properties of Harvested Hypalon Cable Jacket Subjected to Accelerated Thermal Aging

    DOE PAGES

    Duckworth, Robert C.; Kidder, Michelle K.; Aytug, Tolga; ...

    2018-02-27

    We report that for nuclear power plants (NPPs) considering second license renewal for operation beyond 60 years, knowledge of long-term operation, condition monitoring, and viability for the reactor components including reactor pressure vessel, concrete structures, and cable systems is essential. Such knowledge will provide NPP owners/operators with a basis for predicting performance and estimating the costs associated with monitoring or replacement programs for the affected systems. For cable systems that encompass a wide variety of materials, manufacturers, and in-plant locations, accelerated aging of harvested cable jacket and insulation can provide insight into a remaining useful life and methods for monitoring.more » Accelerated thermal aging in air at temperatures between 80°C and 120°C was conducted on a multiconductor control rod drive mechanism cable manufactured by Boston Insulated Wire (BIW). The cable, which had been in service for over 30 years, was jacketed with Hypalon and insulated with ethylene propylene rubber. From elongation at break (EAB) measurements and supporting Arrhenius analysis of the jacket material, an activation energy of 97.84 kJ/mol was estimated, and the time to degradation, as represented by 50% EAB at the expected maximum operating temperature of 45°C, was estimated to be 80 years. These values were slightly below previous measurements on similar BIW Hypalon cable jacket and could be attributed to either in-service degradation or variations in material properties from production variations. Lastly, results from indenter modulus measurements and Fourier transform infrared spectroscopy suggest possible markers that could be beneficial in monitoring cable conditions.« less

  17. Mechanical and Chemical Properties of Harvested Hypalon Cable Jacket Subjected to Accelerated Thermal Aging

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Duckworth, Robert C.; Kidder, Michelle K.; Aytug, Tolga

    We report that for nuclear power plants (NPPs) considering second license renewal for operation beyond 60 years, knowledge of long-term operation, condition monitoring, and viability for the reactor components including reactor pressure vessel, concrete structures, and cable systems is essential. Such knowledge will provide NPP owners/operators with a basis for predicting performance and estimating the costs associated with monitoring or replacement programs for the affected systems. For cable systems that encompass a wide variety of materials, manufacturers, and in-plant locations, accelerated aging of harvested cable jacket and insulation can provide insight into a remaining useful life and methods for monitoring.more » Accelerated thermal aging in air at temperatures between 80°C and 120°C was conducted on a multiconductor control rod drive mechanism cable manufactured by Boston Insulated Wire (BIW). The cable, which had been in service for over 30 years, was jacketed with Hypalon and insulated with ethylene propylene rubber. From elongation at break (EAB) measurements and supporting Arrhenius analysis of the jacket material, an activation energy of 97.84 kJ/mol was estimated, and the time to degradation, as represented by 50% EAB at the expected maximum operating temperature of 45°C, was estimated to be 80 years. These values were slightly below previous measurements on similar BIW Hypalon cable jacket and could be attributed to either in-service degradation or variations in material properties from production variations. Lastly, results from indenter modulus measurements and Fourier transform infrared spectroscopy suggest possible markers that could be beneficial in monitoring cable conditions.« less

  18. Evaluation of Semantic Web Technologies for Storing Computable Definitions of Electronic Health Records Phenotyping Algorithms.

    PubMed

    Papež, Václav; Denaxas, Spiros; Hemingway, Harry

    2017-01-01

    Electronic Health Records are electronic data generated during or as a byproduct of routine patient care. Structured, semi-structured and unstructured EHR offer researchers unprecedented phenotypic breadth and depth and have the potential to accelerate the development of precision medicine approaches at scale. A main EHR use-case is defining phenotyping algorithms that identify disease status, onset and severity. Phenotyping algorithms utilize diagnoses, prescriptions, laboratory tests, symptoms and other elements in order to identify patients with or without a specific trait. No common standardized, structured, computable format exists for storing phenotyping algorithms. The majority of algorithms are stored as human-readable descriptive text documents making their translation to code challenging due to their inherent complexity and hinders their sharing and re-use across the community. In this paper, we evaluate the two key Semantic Web Technologies, the Web Ontology Language and the Resource Description Framework, for enabling computable representations of EHR-driven phenotyping algorithms.

  19. Machine-learning phenotypic classification of bicuspid aortopathy.

    PubMed

    Wojnarski, Charles M; Roselli, Eric E; Idrees, Jay J; Zhu, Yuanjia; Carnes, Theresa A; Lowry, Ashley M; Collier, Patrick H; Griffin, Brian; Ehrlinger, John; Blackstone, Eugene H; Svensson, Lars G; Lytle, Bruce W

    2018-02-01

    Bicuspid aortic valves (BAV) are associated with incompletely characterized aortopathy. Our objectives were to identify distinct patterns of aortopathy using machine-learning methods and characterize their association with valve morphology and patient characteristics. We analyzed preoperative 3-dimensional computed tomography reconstructions for 656 patients with BAV undergoing ascending aorta surgery between January 2002 and January 2014. Unsupervised partitioning around medoids was used to cluster aortic dimensions. Group differences were identified using polytomous random forest analysis. Three distinct aneurysm phenotypes were identified: root (n = 83; 13%), with predominant dilatation at sinuses of Valsalva; ascending (n = 364; 55%), with supracoronary enlargement rarely extending past the brachiocephalic artery; and arch (n = 209; 32%), with aortic arch dilatation. The arch phenotype had the greatest association with right-noncoronary cusp fusion: 29%, versus 13% for ascending and 15% for root phenotypes (P < .0001). Severe valve regurgitation was most prevalent in root phenotype (57%), followed by ascending (34%) and arch phenotypes (25%; P < .0001). Aortic stenosis was most prevalent in arch phenotype (62%), followed by ascending (50%) and root phenotypes (28%; P < .0001). Patient age increased as the extent of aneurysm became more distal (root, 49 years; ascending, 53 years; arch, 57 years; P < .0001), and root phenotype was associated with greater male predominance compared with ascending and arch phenotypes (94%, 76%, and 70%, respectively; P < .0001). Phenotypes were visually recognizable with 94% accuracy. Three distinct phenotypes of bicuspid valve-associated aortopathy were identified using machine-learning methodology. Patient characteristics and valvular dysfunction vary by phenotype, suggesting that the location of aortic pathology may be related to the underlying pathophysiology of this disease. Copyright © 2017 The American

  20. Changes in the PCOS phenotype with age.

    PubMed

    Hsu, Ming-I

    2013-08-01

    Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder of reproductive-age women. The diagnosis of PCOS is mainly based on the following three components: (1) hyperandrogenism, (2) oligo-amenorrhea, and (3) the observation of polycystic ovaries on a sonogram. The comorbidities may include insulin resistance, type II diabetes mellitus, hypertension and cardiovascular disease. Importantly, the diagnostic criteria and complications related to PCOS are age-dependent. Androgen production in women may decrease because of ovarian aging or decreased production by the adrenal glands over time. The prevalence of hirsutism and acne decreases with age. Ovarian volume and follicle number also decrease with age, with the age-related decrease in follicle number seemingly greater than that of ovarian volume. Aging may also be associated with increased risk of insulin resistance and metabolic disturbances. Therefore, these age-related changes may affect the observed incidence and complications of PCOS. In adolescent patients, the criteria described above pose particular diagnostic problems because the characteristics of normal puberty often overlap with the signs and symptoms of PCOS. Hyperandrogenism and chronic anovulation are the primary disturbances in younger women with PCOS; whereas, obesity, insulin resistance, and metabolic disturbances are predominant in older women with PCOS. The deterioration of insulin resistance during the reproductive life of women with PCOS appears to be mainly attributable to the increase in obesity. Therefore, if body weight could be controlled properly, younger hyperandrogenic PCOS women might reduce their risk of insulin resistance and metabolic disturbances later in life. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. Heritability of and Mortality Prediction With a Longevity Phenotype: The Healthy Aging Index

    PubMed Central

    2014-01-01

    Background. Longevity-associated genes may modulate risk for age-related diseases and survival. The Healthy Aging Index (HAI) may be a subphenotype of longevity, which can be constructed in many studies for genetic analysis. We investigated the HAI’s association with survival in the Cardiovascular Health Study and heritability in the Long Life Family Study. Methods. The HAI includes systolic blood pressure, pulmonary vital capacity, creatinine, fasting glucose, and Modified Mini-Mental Status Examination score, each scored 0, 1, or 2 using approximate tertiles and summed from 0 (healthy) to 10 (unhealthy). In Cardiovascular Health Study, the association with mortality and accuracy predicting death were determined with Cox proportional hazards analysis and c-statistics, respectively. In Long Life Family Study, heritability was determined with a variance component–based family analysis using a polygenic model. Results. Cardiovascular Health Study participants with unhealthier index scores (7–10) had 2.62-fold (95% confidence interval: 2.22, 3.10) greater mortality than participants with healthier scores (0–2). The HAI alone predicted death moderately well (c-statistic = 0.643, 95% confidence interval: 0.626, 0.661, p < .0001) and slightly worse than age alone (c-statistic = 0.700, 95% confidence interval: 0.684, 0.717, p < .0001; p < .0001 for comparison of c-statistics). Prediction increased significantly with adjustment for demographics, health behaviors, and clinical comorbidities (c-statistic = 0.780, 95% confidence interval: 0.765, 0.794, p < .0001). In Long Life Family Study, the heritability of the HAI was 0.295 (p < .0001) overall, 0.387 (p < .0001) in probands, and 0.238 (p = .0004) in offspring. Conclusion. The HAI should be investigated further as a candidate phenotype for uncovering longevity-associated genes in humans. PMID:23913930

  2. Accelerated cellular senescence in degenerate intervertebral discs: a possible role in the pathogenesis of intervertebral disc degeneration

    PubMed Central

    Le Maitre, Christine Lyn; Freemont, Anthony John; Hoyland, Judith Alison

    2007-01-01

    Current evidence implicates intervertebral disc degeneration as a major cause of low back pain, although its pathogenesis is poorly understood. Numerous characteristic features of disc degeneration mimic those seen during ageing but appear to occur at an accelerated rate. We hypothesised that this is due to accelerated cellular senescence, which causes fundamental changes in the ability of disc cells to maintain the intervertebral disc (IVD) matrix, thus leading to IVD degeneration. Cells isolated from non-degenerate and degenerate human tissue were assessed for mean telomere length, senescence-associated β-galactosidase (SA-β-gal), and replicative potential. Expression of P16INK4A (increased in cellular senescence) was also investigated in IVD tissue by means of immunohistochemistry. RNA from tissue and cultured cells was used for real-time polymerase chain reaction analysis for matrix metalloproteinase-13, ADAMTS 5 (a disintegrin and metalloprotease with thrombospondin motifs 5), and P16INK4A. Mean telomere length decreased with age in cells from non-degenerate tissue and also decreased with progressive stages of degeneration. In non-degenerate discs, there was an age-related increase in cellular expression of P16INK4A. Cells from degenerate discs (even from young patients) exhibited increased expression of P16INK4A, increased SA-β-gal staining, and a decrease in replicative potential. Importantly, there was a positive correlation between P16INK4A and matrix-degrading enzyme gene expression. Our findings indicate that disc cell senescence occurs in vivo and is accelerated in IVD degeneration. Furthermore, the senescent phenotype is associated with increased catabolism, implicating cellular senescence in the pathogenesis of IVD degeneration. PMID:17498290

  3. Chronic Inflammation: Accelerator of Biological Aging.

    PubMed

    Fougère, Bertrand; Boulanger, Eric; Nourhashémi, Fati; Guyonnet, Sophie; Cesari, Matteo

    2017-09-01

    Biological aging is characterized by a chronic low-grade inflammation level. This chronic phenomenon has been named "inflamm-aging" and is a highly significant risk factor for morbidity and mortality in the older persons. The most common theories of inflamm-aging include redox stress, mitochondrial dysfunction, glycation, deregulation of the immune system, hormonal changes, epigenetic modifications, and dysfunction telomere attrition. Inflamm-aging plays a role in the initiation and progression of age-related diseases such as type II diabetes, Alzheimer's disease, cardiovascular disease, frailty, sarcopenia, osteoporosis, and cancer. This review will cover the identification of pathways that control age-related inflammation across multiple systems and its potential causal role in contributing to adverse health outcomes. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  4. Neutrophils prime a long-lived effector macrophage phenotype that mediates accelerated helminth expulsion

    USDA-ARS?s Scientific Manuscript database

    The innate immune cell populations that mediate metazoan parasite expulsion remain largely undefined. We examined the role of innate cells in the immune response to the nematode parasite Nippostrongylus brasiliensis hypothesizing that they may mediate the markedly accelerated CD4+ T cell-independen...

  5. Towards A Model-Based Prognostics Methodology for Electrolytic Capacitors: A Case Study Based on Electrical Overstress Accelerated Aging

    NASA Technical Reports Server (NTRS)

    Celaya, Jose R.; Kulkarni, Chetan S.; Biswas, Gautam; Goebel, Kai

    2012-01-01

    A remaining useful life prediction methodology for electrolytic capacitors is presented. This methodology is based on the Kalman filter framework and an empirical degradation model. Electrolytic capacitors are used in several applications ranging from power supplies on critical avionics equipment to power drivers for electro-mechanical actuators. These devices are known for their comparatively low reliability and given their criticality in electronics subsystems they are a good candidate for component level prognostics and health management. Prognostics provides a way to assess remaining useful life of a capacitor based on its current state of health and its anticipated future usage and operational conditions. We present here also, experimental results of an accelerated aging test under electrical stresses. The data obtained in this test form the basis for a remaining life prediction algorithm where a model of the degradation process is suggested. This preliminary remaining life prediction algorithm serves as a demonstration of how prognostics methodologies could be used for electrolytic capacitors. In addition, the use degradation progression data from accelerated aging, provides an avenue for validation of applications of the Kalman filter based prognostics methods typically used for remaining useful life predictions in other applications.

  6. Epithelial phenotype and the RPE: is the answer blowing in the Wnt?

    PubMed

    Burke, Janice M

    2008-11-01

    Cells of the human retinal pigment epithelium (RPE) have a regular epithelial cell shape within the tissue in situ, but for reasons that remain elusive the RPE shows an incomplete and variable ability to re-develop an epithelial phenotype after propagation in vitro. In other epithelial cell cultures, formation of an adherens junction (AJ) composed of E-cadherin plays an important early inductive role in epithelial morphogenesis, but E-cadherin is largely absent from the RPE. In this review, the contribution of cadherins, both minor (E-cadherin) and major (N-cadherin), to RPE phenotype development is discussed. Emphasis is placed on the importance for future studies of actin cytoskeletal remodeling during assembly of the AJ, which in epithelial cells results in an actin organization that is characteristically zonular. Other markers of RPE phenotype that are used to gauge the maturation state of RPE cultures including tissue-specific protein expression, protein polarity, and pigmentation are described. An argument is made that RPE epithelial phenotype, cadherin-based cell-cell adhesion and melanization are linked by a common signaling pathway: the Wnt/beta-catenin pathway. Analyzing this pathway and its intersecting signaling networks is suggested as a useful framework for dissecting the steps in RPE morphogenesis. Also discussed is the effect of aging on RPE phenotype. Preliminary evidence is provided to suggest that light-induced sub-lethal oxidative stress to cultured ARPE-19 cells impairs organelle motility. Organelle translocation, which is mediated by stress-susceptible cytoskeletal scaffolds, is an essential process in cell phenotype development and retention. The observation of impaired organelle motility therefore raises the possibility that low levels of stress, which are believed to accompany RPE aging, may produce subtle disruptions of cell phenotype. Over time these would be expected to diminish the support functions performed by the RPE on behalf of

  7. Crop 3D-a LiDAR based platform for 3D high-throughput crop phenotyping.

    PubMed

    Guo, Qinghua; Wu, Fangfang; Pang, Shuxin; Zhao, Xiaoqian; Chen, Linhai; Liu, Jin; Xue, Baolin; Xu, Guangcai; Li, Le; Jing, Haichun; Chu, Chengcai

    2018-03-01

    With the growing population and the reducing arable land, breeding has been considered as an effective way to solve the food crisis. As an important part in breeding, high-throughput phenotyping can accelerate the breeding process effectively. Light detection and ranging (LiDAR) is an active remote sensing technology that is capable of acquiring three-dimensional (3D) data accurately, and has a great potential in crop phenotyping. Given that crop phenotyping based on LiDAR technology is not common in China, we developed a high-throughput crop phenotyping platform, named Crop 3D, which integrated LiDAR sensor, high-resolution camera, thermal camera and hyperspectral imager. Compared with traditional crop phenotyping techniques, Crop 3D can acquire multi-source phenotypic data in the whole crop growing period and extract plant height, plant width, leaf length, leaf width, leaf area, leaf inclination angle and other parameters for plant biology and genomics analysis. In this paper, we described the designs, functions and testing results of the Crop 3D platform, and briefly discussed the potential applications and future development of the platform in phenotyping. We concluded that platforms integrating LiDAR and traditional remote sensing techniques might be the future trend of crop high-throughput phenotyping.

  8. Feast and famine: Adipose tissue adaptations for healthy aging.

    PubMed

    Lettieri Barbato, Daniele; Aquilano, Katia

    2016-07-01

    Proper adipose tissue function controls energy balance with favourable effects on metabolic health and longevity. The molecular and metabolic asset of adipose tissue quickly and dynamically readapts in response to nutrient fluctuations. Once delivered into cells, nutrients are managed by mitochondria that represent a key bioenergetics node. A persistent nutrient overload generates mitochondrial exhaustion and uncontrolled reactive oxygen species ((mt)ROS) production. In adipocytes, metabolic/molecular reorganization is triggered culminating in the acquirement of a hypertrophic and hypersecretory phenotype that accelerates aging. Conversely, dietary regimens such as caloric restriction or time-controlled fasting endorse mitochondrial functionality and (mt)ROS-mediated signalling, thus promoting geroprotection. In this perspective view, we argued some important molecular and metabolic aspects related to adipocyte response to nutrient stress. Finally we delineated hypothetical routes by which molecularly and metabolically readapted adipose tissue promotes healthy aging. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Accelerated Evolution in Distinctive Species Reveals Candidate Elements for Clinically Relevant Traits, Including Mutation and Cancer Resistance.

    PubMed

    Ferris, Elliott; Abegglen, Lisa M; Schiffman, Joshua D; Gregg, Christopher

    2018-03-06

    The identity of most functional elements in the mammalian genome and the phenotypes they impact are unclear. Here, we perform a genome-wide comparative analysis of patterns of accelerated evolution in species with highly distinctive traits to discover candidate functional elements for clinically important phenotypes. We identify accelerated regions (ARs) in the elephant, hibernating bat, orca, dolphin, naked mole rat, and thirteen-lined ground squirrel lineages in mammalian conserved regions, uncovering ∼33,000 elements that bind hundreds of different regulatory proteins in humans and mice. ARs in the elephant, the largest land mammal, are uniquely enriched near elephant DNA damage response genes. The genomic hotspot for elephant ARs is the E3 ligase subunit of the Fanconi anemia complex, a master regulator of DNA repair. Additionally, ARs in the six species are associated with specific human clinical phenotypes that have apparent concordance with overt traits in each species. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  10. Increased T Cell Immunosenescence and Accelerated Maturation Phenotypes in Older Kidney Transplant Recipients.

    PubMed

    Schaenman, J M; Rossetti, M; Sidwell, T; Groysberg, V; Sunga, G; Korin, Y; Liang, E; Zhou, X; Abdallah, B; Lum, E; Bunnapradist, S; Pham, T; Danovitch, G; Reed, E F

    2018-06-15

    Older kidney transplant recipients experience increased rates of infection and death, and less rejection, compared with younger patients. However, little is known about immune dysfunction in older compared with younger kidney transplant recipients and whether it is associated with infection. We evaluated T cell phenotypes including maturation, immune senescence, and exhaustion in a novel investigation into differences in older compared with younger patients receiving identical immune suppression regimens. We evaluated PBMC from 60 kidney transplant recipients (23 older and 37 matched younger patients) by multiparameter immune phenotyping. Older kidney transplant recipients demonstrated decreased frequency of naïve CD4+ and CD8+ T cells, and increased frequency of terminally differentiated, immune senescent, and NK T cells expressing KLRG1. There was a trend towards increased frequency of T cell immune senescence in patients experiencing infection in the first year after transplantation, which reached statistical significance in a multivariate analysis. This pilot study reveals immune dysfunction in older compared with younger transplant recipients, and suggests a likely mechanism for increased vulnerability to infection. The ability to assess T cell maturation and immune senescence in transplant recipients offers the potential for risk stratification and customization of immune suppression to prevent infection and rejection after transplantation. Copyright © 2018. Published by Elsevier Inc.

  11. Environmental Heat and Salt Stress Induce Transgenerational Phenotypic Changes in Arabidopsis thaliana

    PubMed Central

    Suter, Léonie; Widmer, Alex

    2013-01-01

    Plants that can adapt their phenotype may be more likely to survive changing environmental conditions. Heritable epigenetic variation could provide a way to rapidly adapt to such changes. Here we tested whether environmental stress induces heritable, potentially adaptive phenotypic changes independent of genetic variation over few generations in Arabidopsis thaliana. We grew two accessions (Col-0, Sha-0) of A. thaliana for three generations under salt, heat and control conditions and tested for induced heritable phenotypic changes in the fourth generation (G4) and in reciprocal F1 hybrids generated in generation three. Using these crosses we further tested whether phenotypic changes were maternally or paternally transmitted. In generation five (G5), we assessed whether phenotypic effects persisted over two generations in the absence of stress. We found that exposure to heat stress in previous generations accelerated flowering under G4 control conditions in Sha-0, but heritable effects disappeared in G5 after two generations without stress exposure. Previous exposure to salt stress increased salt tolerance in one of two reciprocal F1 hybrids. Transgenerational effects were maternally and paternally inherited. Lacking genetic variability, maternal and paternal inheritance and reversibility of transgenerational effects together indicate that stress can induce heritable, potentially adaptive phenotypic changes, probably through epigenetic mechanisms. These effects were strongly dependent on plant genotype and may not be a general response to stress in A. thaliana. PMID:23585834

  12. (1)H-MRS in glutaric aciduria type 1: impact of biochemical phenotype and age on the cerebral accumulation of neurotoxic metabolites.

    PubMed

    Harting, Inga; Boy, Nikolas; Heringer, Jana; Seitz, Angelika; Bendszus, Martin; Pouwels, Petra J W; Kölker, Stefan

    2015-09-01

    In glutaric aciduria type 1 (GA1) the neurotoxic metabolites glutaric acid (GA) and 3-hydroxyglutaric acid (3-OH-GA) accumulate within the brain. Due to limited efflux across the blood-brain-barrier biochemical monitoring of intracerebrally accumulating toxic metabolites is as yet not possible. To investigate brain metabolic patterns in glutaric aciduria type 1 using (1)H magnetic resonance spectroscopy ((1)H-MRS) with focus on detecting the disease-related neurotoxic metabolites GA and 3-OH-GA. Short echo time (1)H-MRS was performed in 13 treated metabolically stable patients. Twenty-one white matter and 16 basal ganglia spectra from 12 patients (age range 7 months - 22 years) were included. Subgroups based on age, biochemical phenotype and/or associated MRI changes were compared with control spectra. GA was elevated in white matter of patients. 3-OH-GA was elevated in white matter of older patients with associated signal changes on MRI, which was structurally characterized by decreased creatine and phosphocreatine (tCr) and elevated choline (Cho). Metabolite changes differed with biochemical phenotype and disease duration: Low excretors with up to 30% residual enzyme activity had only mildly, non-significantly elevated GA and mildly subnormal N-acetylaspartate (tNAA). High excretors with complete lack of enzyme activity had significantly increased GA, tNAA was mildly subnormal in younger and decreased in older high excretors. GA and 3-OH-GA are detectable by in vivo (1)H-MRS, which might finally allow biochemical follow-up monitoring of intracerebrally accumulating neurotoxic metabolites in GA1. A high excreting phenotype appears to be a risk factor for cerebral GA accumulation and progressive neuroaxonal compromise despite a similar clinical course in younger high and low excreting patients. This might have consequences for long-term outcome.

  13. Accelerated Age-Dependent Hippocampal Volume Loss in Parkinson Disease With Mild Cognitive Impairment.

    PubMed

    Schneider, Christine B; Donix, Markus; Linse, Katharina; Werner, Annett; Fauser, Mareike; Klingelhoefer, Lisa; Löhle, Matthias; von Kummer, Rüdiger; Reichmann, Heinz; Storch, Alexander

    2017-09-01

    Patients with Parkinson disease are at high risk of developing dementia. During the course of the disease, a substantial number of patients will experience a cognitive decline, indicating the dynamics of the underlying neuropathology. Magnetic resonance imaging (MRI) has become increasingly useful for identifying structural characteristics in radiological brain anatomy existing prior to clinical symptoms. Whether these changes reflect pathology, whether they are aging related, or both often remains unclear. We hypothesized that aging-associated brain structural changes would be more pronounced in the hippocampal region among patients with Parkinson disease having mild cognitive deficits relative to cognitively unimpaired patients. Using MRI, we investigated 30 cognitively healthy patients with Parkinson disease and 33 patients with nondemented Parkinson disease having mild cognitive impairment. All participants underwent structural MRI scanning and extensive clinical and neuropsychological assessments. Irrespective of the study participants' cognitive status, older age was associated with reduced cortical thickness in various neocortical regions. Having mild cognitive impairment was not associated with an increased rate of cortical thinning or volume loss in these regions, except in the hippocampus bilaterally. Patients with Parkinson disease having mild cognitive impairment show an accelerated age-dependent hippocampal volume loss when compared with cognitively healthy patients with Parkinson disease. This may indicate pathological processes in a key region for memory functioning in patients with Parkinson disease at risk of developing dementia. Structural MRI of the hippocampal region could potentially contribute to identifying patients who should receive early treatment aimed at delaying the clinical onset of dementia.

  14. Hypertriglyceridemic waist-to-height ratio phenotype: association with atherogenic lipid profile in Han adolescents.

    PubMed

    Ma, Chun-ming; Liu, Xiao-li; Yin, Fu-Zai; Gao, Guo-qin; Wang, Rui; Lu, Qiang

    2015-09-01

    Hypertriglyceridemic waist (HW) phenotype was associated with an atherogenic lipid profile in adolescents. But unlike adults, the cutoffs of waist circumference are age- and gender-specific standards and are less feasible for non-professional use. The present study tested the hypothesis that simple variables, such as waist-to-height ratio (WHtR) and serum triacylglycerol (TG) concentrations, could be used as screening tools for the identification of adolescents characterized by atherogenic lipid profile. In 2006, anthropometric and biochemical measurements were assessed in a cross-sectional population-based study of 3136 Han adolescents, aged 13-17 years. The hypertriglyceridemic waist-to-height ratio (HWHtR) phenotype was defined as serum TG concentrations ≥1.47 mmol/L and WHtR ≥0.48 for boys and ≥0.46 for girls. Hypercholesterolemia (total cholesterol ≥5.18 mmol/L), high low-density lipoprotein cholesterol (LDL-C ≥3.37 mmol/L), low high-density lipoprotein cholesterol (HDL-C <1.03 mmol/L), and high non-HDL-C (≥3.76 mmol/L) were considered as atherogenic lipid profiles. After control for age and sex, adolescents with the HWHtR phenotype were more likely to have hypercholesterolemia (odds ratio (OR) = 7.8, 95 % confidence interval (CI) = 3.5-17.3, P < 0.001), high LDL-C (OR = 9.4, 95 % CI = 2.8-31.2, P < 0.001), low HDL-C (OR = 10.8, 95 % CI = 6.9-17.0, P < 0.001), and high non-HDL-C (OR = 22.9, 95 % CI = 10.0-52.2, P < 0.001) than those adolescents with normal WHtR and normal serum TG concentrations. The present study demonstrates that HWHtR phenotype is a simple marker for identifying adolescents with atherogenic lipid profile. Compared with HW phenotype, HWHtR phenotype is a non-age-dependent index with higher applicability to screen for cardiovascular risk factors in adolescents. • The hypertriglyceridemic waist phenotype is represented by the simultaneous presence of elevated serum triacylglycerol

  15. Comparison of cable ageing

    NASA Astrophysics Data System (ADS)

    Plaček, Vít; Kohout, Tomáš

    2010-03-01

    Two cable types, which currently are used in nuclear power plants (NPP) and which are composed by jacket/insulation materials, i.e. PVC/PVC and PVC/PE, were exposed to accelerated ageing conditions, in order to simulate their behavior after 10 years in service. The cables were aged under two different test conditions: With relatively high accelerating ageing speed:Radiation ageing was carried out at room temperature at a dose rate of 2900 Gy/h, followed by thermal ageing at 100 °C. This accelerated ageing condition was fairly fast, but still in compliance with the standards. With moderate ageing speed:The radiation and thermal ageing was performed simultaneously (superimposed) at a dose rate of 2.7-3.7Gy/h and a temperature of 68-70 °C. Such a test condition seems to be very close to the radiation and temperature impact onto the cables in the real NPP service. Finally, mechanical properties were measured to characterize the ageing status of the cables. The purpose of this study was to compare degradation effects, derived from both ageing methods, and to demonstrate that results obtained from high values of accelerating parameters and from fast ageing simulation can be very different from reality. The observed results corroborated this assumption.

  16. Endothelial transplantation rejuvenates aged hematopoietic stem cell function

    PubMed Central

    Poulos, Michael G.; Gutkin, Michael C.; Llanos, Pierre; Gilleran, Katherine; Rabbany, Sina Y.; Butler, Jason M.

    2017-01-01

    Age-related changes in the hematopoietic compartment are primarily attributed to cell-intrinsic alterations in hematopoietic stem cells (HSCs); however, the contribution of the aged microenvironment has not been adequately evaluated. Understanding the role of the bone marrow (BM) microenvironment in supporting HSC function may prove to be beneficial in treating age-related functional hematopoietic decline. Here, we determined that aging of endothelial cells (ECs), a critical component of the BM microenvironment, was sufficient to drive hematopoietic aging phenotypes in young HSCs. We used an ex vivo hematopoietic stem and progenitor cell/EC (HSPC/EC) coculture system as well as in vivo EC infusions following myelosuppressive injury in mice to demonstrate that aged ECs impair the repopulating activity of young HSCs and impart a myeloid bias. Conversely, young ECs restored the repopulating capacity of aged HSCs but were unable to reverse the intrinsic myeloid bias. Infusion of young, HSC-supportive BM ECs enhanced hematopoietic recovery following myelosuppressive injury and restored endogenous HSC function in aged mice. Coinfusion of young ECs augmented aged HSC engraftment and enhanced overall survival in lethally irradiated mice by mitigating damage to the BM vascular microenvironment. These data lay the groundwork for the exploration of EC therapies that can serve as adjuvant modalities to enhance HSC engraftment and accelerate hematopoietic recovery in the elderly population following myelosuppressive regimens. PMID:29035282

  17. Epistasis can accelerate adaptive diversification in haploid asexual populations.

    PubMed

    Griswold, Cortland K

    2015-03-07

    A fundamental goal of the biological sciences is to determine processes that facilitate the evolution of diversity. These processes can be separated into ecological, physiological, developmental and genetic. An ecological process that facilitates diversification is frequency-dependent selection caused by competition. Models of frequency-dependent adaptive diversification have generally assumed a genetic basis of phenotype that is non-epistatic. Here, we present a model that indicates diversification is accelerated by an epistatic basis of phenotype in combination with a competition model that invokes frequency-dependent selection. Our model makes use of a genealogical model of epistasis and insights into the effects of balancing selection on the genealogical structure of a population to understand how epistasis can facilitate diversification. The finding that epistasis facilitates diversification may be informative with respect to empirical results that indicate an epistatic basis of phenotype in experimental bacterial populations that experienced adaptive diversification. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

  18. A Novel Lung Disease Phenotype Adjusted for Mortality Attrition for Cystic Fibrosis Genetic Modifier Studies

    PubMed Central

    Taylor, Chelsea; Commander, Clayton W.; Collaco, Joseph M.; Strug, Lisa J.; Li, Weili; Wright, Fred A.; Webel, Aaron D.; Pace, Rhonda G.; Stonebraker, Jaclyn R.; Naughton, Kathleen; Dorfman, Ruslan; Sandford, Andrew; Blackman, Scott M.; Berthiaume, Yves; Paré, Peter; Drumm, Mitchell L.; Zielenski, Julian; Durie, Peter; Cutting, Garry R.; Knowles, Michael R.; Corey, Mary

    2011-01-01

    SUMMARY Genetic studies of lung disease in Cystic Fibrosis are hampered by the lack of a severity measure that accounts for chronic disease progression and mortality attrition. Further, combining analyses across studies requires common phenotypes that are robust to study design and patient ascertainment. Using data from the North American Cystic Fibrosis Modifier Consortium (Canadian Consortium for CF Genetic Studies, Johns Hopkins University CF Twin and Sibling Study, and University of North Carolina/Case Western Reserve University Gene Modifier Study), the authors calculated age-specific CF percentile values of FEV1 which were adjusted for CF age-specific mortality data. The phenotype was computed for 2061 patients representing the Canadian CF population, 1137 extreme phenotype patients in the UNC/Case Western study, and 1323 patients from multiple CF sib families in the CF Twin and Sibling Study. Despite differences in ascertainment and median age, our phenotype score was distributed in all three samples in a manner consistent with ascertainment differences, reflecting the lung disease severity of each individual in the underlying population. The new phenotype score was highly correlated with the previously recommended complex phenotype, but the new phenotype is more robust for shorter follow-up and for extreme ages. A disease progression and mortality adjusted phenotype reduces the need for stratification or additional covariates, increasing statistical power and avoiding possible distortions. This approach will facilitate large scale genetic and environmental epidemiological studies which will provide targeted therapeutic pathways for the clinical benefit of patients with CF. PMID:21462361

  19. An XML-based interchange format for genotype-phenotype data.

    PubMed

    Whirl-Carrillo, M; Woon, M; Thorn, C F; Klein, T E; Altman, R B

    2008-02-01

    Recent advances in high-throughput genotyping and phenotyping have accelerated the creation of pharmacogenomic data. Consequently, the community requires standard formats to exchange large amounts of diverse information. To facilitate the transfer of pharmacogenomics data between databases and analysis packages, we have created a standard XML (eXtensible Markup Language) schema that describes both genotype and phenotype data as well as associated metadata. The schema accommodates information regarding genes, drugs, diseases, experimental methods, genomic/RNA/protein sequences, subjects, subject groups, and literature. The Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB; www.pharmgkb.org) has used this XML schema for more than 5 years to accept and process submissions containing more than 1,814,139 SNPs on 20,797 subjects using 8,975 assays. Although developed in the context of pharmacogenomics, the schema is of general utility for exchange of genotype and phenotype data. We have written syntactic and semantic validators to check documents using this format. The schema and code for validation is available to the community at http://www.pharmgkb.org/schema/index.html (last accessed: 8 October 2007). (c) 2007 Wiley-Liss, Inc.

  20. Chemical vs. Physical Acceleration of Cement Hydration

    PubMed Central

    Bentz, Dale P.; Zunino, Franco; Lootens, Didier

    2016-01-01

    Cold weather concreting often requires the use of chemical accelerators to speed up the hydration reactions of the cement, so that setting and early-age strength development will occur in a timely manner. While calcium chloride (dihydrate – CaCl2·2H2O) is the most commonly used chemical accelerator, recent research using fine limestone powders has indicated their high proficiency for physically accelerating early-age hydration and reducing setting times. This paper presents a comparative study of the efficiency of these two approaches in accelerating hydration (as assessed via isothermal calorimetry), reducing setting times (Vicat needle), and increasing early-age mortar cube strength (1 d and 7 d). Both the CaCl2 and the fine limestone powder are used to replace a portion of the finest sand in the mortar mixtures, while keeping both the water-to-cement ratio and volume fractions of water and cement constant. Studies are conducted at 73.4 °F (23°C) and 50 °F (10 °C), so that activation energies can be estimated for the hydration and setting processes. Because the mechanisms of acceleration of the CaCl2 and limestone powder are different, a hybrid mixture with 1 % CaCl2 and 20 % limestone powder (by mass of cement) is also investigated. Both technologies are found to be viable options for reducing setting times and increasing early-age strengths, and it is hoped that concrete producers and contractors will consider the addition of fine limestone powder to their toolbox of techniques for assuring performance in cold weather and other concreting conditions where acceleration may be needed. PMID:28077884

  1. Fat-specific Dicer deficiency accelerates aging and mitigates several effects of dietary restriction in mice.

    PubMed

    Reis, Felipe C G; Branquinho, Jéssica L O; Brandão, Bruna B; Guerra, Beatriz A; Silva, Ismael D; Frontini, Andrea; Thomou, Thomas; Sartini, Loris; Cinti, Saverio; Kahn, C Ronald; Festuccia, William T; Kowaltowski, Alicia J; Mori, Marcelo A

    2016-06-01

    Aging increases the risk of type 2 diabetes, and this can be prevented by dietary restriction (DR). We have previously shown that DR inhibits the downregulation of miRNAs and their processing enzymes - mainly Dicer - that occurs with aging in mouse white adipose tissue (WAT). Here we used fat-specific Dicer knockout mice (AdicerKO) to understand the contributions of adipose tissue Dicer to the metabolic effects of aging and DR. Metabolomic data uncovered a clear distinction between the serum metabolite profiles of Lox control and AdicerKO mice, with a notable elevation of branched-chain amino acids (BCAA) in AdicerKO. These profiles were associated with reduced oxidative metabolism and increased lactate in WAT of AdicerKO mice and were accompanied by structural and functional changes in mitochondria, particularly under DR. AdicerKO mice displayed increased mTORC1 activation in WAT and skeletal muscle, where Dicer expression is not affected. This was accompanied by accelerated age-associated insulin resistance and premature mortality. Moreover, DR-induced insulin sensitivity was abrogated in AdicerKO mice. This was reverted by rapamycin injection, demonstrating that insulin resistance in AdicerKO mice is caused by mTORC1 hyperactivation. Our study evidences a DR-modulated role for WAT Dicer in controlling metabolism and insulin resistance.

  2. Fat-specific Dicer deficiency accelerates aging and mitigates several effects of dietary restriction in mice

    PubMed Central

    Reis, Felipe C. G.; Branquinho, Jéssica L. O.; Brandão, Bruna B.; Guerra, Beatriz A.; Silva, Ismael D.; Frontini, Andrea; Thomou, Thomas; Sartini, Loris; Cinti, Saverio; Kahn, C. Ronald; Festuccia, William T.; Kowaltowski, Alicia J.; Mori, Marcelo A.

    2016-01-01

    Aging increases the risk of type 2 diabetes, and this can be prevented by dietary restriction (DR). We have previously shown that DR inhibits the downregulation of miRNAs and their processing enzymes - mainly Dicer - that occurs with aging in mouse white adipose tissue (WAT). Here we used fat-specific Dicer knockout mice (AdicerKO) to understand the contributions of adipose tissue Dicer to the metabolic effects of aging and DR. Metabolomic data uncovered a clear distinction between the serum metabolite profiles of Lox control and AdicerKO mice, with a notable elevation of branched-chain amino acids (BCAA) in AdicerKO. These profiles were associated with reduced oxidative metabolism and increased lactate in WAT of AdicerKO mice and were accompanied by structural and functional changes in mitochondria, particularly under DR. AdicerKO mice displayed increased mTORC1 activation in WAT and skeletal muscle, where Dicer expression is not affected. This was accompanied by accelerated age-associated insulin resistance and premature mortality. Moreover, DR-induced insulin sensitivity was abrogated in AdicerKO mice. This was reverted by rapamycin injection, demonstrating that insulin resistance in AdicerKO mice is caused by mTORC1 hyperactivation. Our study evidences a DR-modulated role for WAT Dicer in controlling metabolism and insulin resistance. PMID:27241713

  3. Global urban signatures of phenotypic change in animal and plant populations

    PubMed Central

    Correa, Cristian; Marzluff, John M.; Hendry, Andrew P.; Palkovacs, Eric P.; Hunt, Victoria M.; Apgar, Travis M.; Zhou, Yuyu

    2017-01-01

    Humans challenge the phenotypic, genetic, and cultural makeup of species by affecting the fitness landscapes on which they evolve. Recent studies show that cities might play a major role in contemporary evolution by accelerating phenotypic changes in wildlife, including animals, plants, fungi, and other organisms. Many studies of ecoevolutionary change have focused on anthropogenic drivers, but none of these studies has specifically examined the role that urbanization plays in ecoevolution or explicitly examined its mechanisms. This paper presents evidence on the mechanisms linking urban development patterns to rapid evolutionary changes for species that play important functional roles in communities and ecosystems. Through a metaanalysis of experimental and observational studies reporting more than 1,600 phenotypic changes in species across multiple regions, we ask whether we can discriminate an urban signature of phenotypic change beyond the established natural baselines and other anthropogenic signals. We then assess the relative impact of five types of urban disturbances including habitat modifications, biotic interactions, habitat heterogeneity, novel disturbances, and social interactions. Our study shows a clear urban signal; rates of phenotypic change are greater in urbanizing systems compared with natural and nonurban anthropogenic systems. By explicitly linking urban development to traits that affect ecosystem function, we can map potential ecoevolutionary implications of emerging patterns of urban agglomerations and uncover insights for maintaining key ecosystem functions upon which the sustainability of human well-being depends. PMID:28049817

  4. Global urban signatures of phenotypic change in animal and plant populations.

    PubMed

    Alberti, Marina; Correa, Cristian; Marzluff, John M; Hendry, Andrew P; Palkovacs, Eric P; Gotanda, Kiyoko M; Hunt, Victoria M; Apgar, Travis M; Zhou, Yuyu

    2017-08-22

    Humans challenge the phenotypic, genetic, and cultural makeup of species by affecting the fitness landscapes on which they evolve. Recent studies show that cities might play a major role in contemporary evolution by accelerating phenotypic changes in wildlife, including animals, plants, fungi, and other organisms. Many studies of ecoevolutionary change have focused on anthropogenic drivers, but none of these studies has specifically examined the role that urbanization plays in ecoevolution or explicitly examined its mechanisms. This paper presents evidence on the mechanisms linking urban development patterns to rapid evolutionary changes for species that play important functional roles in communities and ecosystems. Through a metaanalysis of experimental and observational studies reporting more than 1,600 phenotypic changes in species across multiple regions, we ask whether we can discriminate an urban signature of phenotypic change beyond the established natural baselines and other anthropogenic signals. We then assess the relative impact of five types of urban disturbances including habitat modifications, biotic interactions, habitat heterogeneity, novel disturbances, and social interactions. Our study shows a clear urban signal; rates of phenotypic change are greater in urbanizing systems compared with natural and nonurban anthropogenic systems. By explicitly linking urban development to traits that affect ecosystem function, we can map potential ecoevolutionary implications of emerging patterns of urban agglomerations and uncover insights for maintaining key ecosystem functions upon which the sustainability of human well-being depends.

  5. Evolution on neutral networks accelerates the ticking rate of the molecular clock.

    PubMed

    Manrubia, Susanna; Cuesta, José A

    2015-01-06

    Large sets of genotypes give rise to the same phenotype, because phenotypic expression is highly redundant. Accordingly, a population can accept mutations without altering its phenotype, as long as the genotype mutates into another one on the same set. By linking every pair of genotypes that are mutually accessible through mutation, genotypes organize themselves into neutral networks (NNs). These networks are known to be heterogeneous and assortative, and these properties affect the evolutionary dynamics of the population. By studying the dynamics of populations on NNs with arbitrary topology, we analyse the effect of assortativity, of NN (phenotype) fitness and of network size. We find that the probability that the population leaves the network is smaller the longer the time spent on it. This progressive 'phenotypic entrapment' entails a systematic increase in the overdispersion of the process with time and an acceleration in the fixation rate of neutral mutations. We also quantify the variation of these effects with the size of the phenotype and with its fitness relative to that of neighbouring alternatives. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

  6. Age-related behavioral phenotype of an astrocytic monoamine oxidase-B transgenic mouse model of Parkinson's disease.

    PubMed

    Lieu, Christopher A; Chinta, Shankar J; Rane, Anand; Andersen, Julie K

    2013-01-01

    We have previously shown that increases in astrocytic monoamine oxidase-B (MAO-B) expression, mimicking that which occurs with aging and in neurodegenerative disease, in a doxycycline (dox)-inducible transgenic mouse model evokes neuropathological similarities to what is observed in the human parkinsonian brain. Additional behavioral and neuropathological studies could provide further validation for its usage as a model for Parkinson's disease (PD). In the present study, we utilized a battery of behavioral tests to evaluate age-related phenotype in this model. In the open field test, we found that dox-induction impaired motor ability with decreases in movement and ambulatory function as well as diminished stereotypical, repetitive movement episodes in both young and old mice. Older mice also showed decreased motor performance in the pole test when compared to younger mice. Furthermore, dox-induced older mice displayed severe hindlimb clasping and the most significant loss of dopamine (DA) in the striatum when compared to young and non-induced animals. Additionally, increased MAO-B activity significantly correlated with decreased expression of striatal DA. The results of our study further confirms that the dox-inducible astrocytic MAO-B transgenic mouse displays similar age-related behavioral and neuropathological features to other models of PD, and could serve as a useful tool to study PD pathophysiology and for the evaluation of therapeutic interventions.

  7. Explosive and pyrotechnic aging demonstration

    NASA Technical Reports Server (NTRS)

    Rouch, L. L., Jr.; Maycock, J. N.

    1976-01-01

    The survivability was experimentally verified of fine selected explosive and pyrotechnic propellant materials when subjected to sterilization, and prolonged exposure to space environments. This verification included thermal characterization, sterilization heat cycling, sublimation measurements, isothermal decomposition measurements, and accelerated aging at a preselected elevated temperature. Temperatures chosen for sublimation and isothermal decomposition measurements were those in which the decomposition processess occurring would be the same as those taking place in real-time aging. The elevated temperature selected (84 C) for accelerated aging was based upon the parameters calculated from the kinetic data obtained in the isothermal measurement tests and was such that one month of accelerated aging in the laboratory approximated one year of real-time aging at 66 C. Results indicate that HNS-IIA, pure PbN6, KDNBF, and Zr/KC10 are capable of withstanding sterilization. The accelerated aging tests indicated that unsterilized HNS-IIA and Zr/KC104 can withstand the 10 year, elevated temperature exposure, pure PbN6 and KDNBF exhibit small weight losses (less than 2 percent) and B/KC104 exhibits significant changes in its thermal characteristics. Accelerated aging tests after sterilization indicated that only HNS-IIA exhibited high stability.

  8. Soiling of building envelope surfaces and its effect on solar reflectance – Part III: Interlaboratory study of an accelerated aging method for roofing materials

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Sleiman, Mohamad; Chen, Sharon; Gilbert, Haley E.

    A laboratory method to simulate natural exposure of roofing materials has been reported in a companion article. Here in the current article, we describe the results of an international, nine-participant interlaboratory study (ILS) conducted in accordance with ASTM Standard E691-09 to establish the precision and reproducibility of this protocol. The accelerated soiling and weathering method was applied four times by each laboratory to replicate coupons of 12 products representing a wide variety of roofing categories (single-ply membrane, factory-applied coating (on metal), bare metal, field-applied coating, asphalt shingle, modified-bitumen cap sheet, clay tile, and concrete tile). Participants reported initial and laboratory-agedmore » values of solar reflectance and thermal emittance. Measured solar reflectances were consistent within and across eight of the nine participating laboratories. Measured thermal emittances reported by six participants exhibited comparable consistency. For solar reflectance, the accelerated aging method is both repeatable and reproducible within an acceptable range of standard deviations: the repeatability standard deviation sr ranged from 0.008 to 0.015 (relative standard deviation of 1.2–2.1%) and the reproducibility standard deviation sR ranged from 0.022 to 0.036 (relative standard deviation of 3.2–5.8%). The ILS confirmed that the accelerated aging method can be reproduced by multiple independent laboratories with acceptable precision. In conclusion, this study supports the adoption of the accelerated aging practice to speed the evaluation and performance rating of new cool roofing materials.« less

  9. Comparison of clinical explants and accelerated hydrolytic aging to improve biostability assessment of silicone-based polyurethanes.

    PubMed

    Cosgriff-Hernandez, Elizabeth; Tkatchouk, Ekaterina; Touchet, Tyler; Sears, Nick; Kishan, Alysha; Jenney, Christopher; Padsalgikar, Ajay D; Chen, Emily

    2016-07-01

    Although silicone-based polyurethanes have demonstrated increased oxidative stability, there have been conflicting reports of the long-term hydrolytic stability of Optim™ and PurSil(®) 35 based on recent temperature-accelerated hydrolysis studies. The goal of the current study was to identify in vitro-in vivo correlations to determine the relevance of this accelerated in vitro model for predicting clinical outcomes. Temperature-accelerated hydrolytic aging of three commonly used cardiac lead insulation materials, Optim™, Elasthane™ 55D, Elasthane™ 80A, and a related silicone-polyurethane, PurSil(®) 35, was performed. After 1 year at 85°C, similar losses in Mn and Mz were observed for the poly(ether urethanes), but an increase in Mz loss as compared to Mn loss was observed for the silicone-based polyurethanes. A similar trend of increased Mz loss as compared to Mn loss was observed in explanted Optim™ leads after 2-3 years; however, no statistically significant Mn loss was detected between 2-3 and 7-8 years of implantation. Given this preferential loss of high molecular weight chains, it was hypothesized that the observed differences between the polyurethanes were due to allophanate dissociation rather than backbone chain scission. Following full dissociation of the small percentage of allophanates in vivo, the observed molecular weight stability and proven clinical performance of Optim™ was attributed to the well-documented stability of the urethane bond under physiological conditions. This allophanate dissociation reaction is incompatible with the first order mechanism proposed in previous temperature-accelerated hydrolysis studies and may be the reason for the model's inaccurate prediction of significant and progressive molecular weight loss in vivo. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1805-1816, 2016. © 2016 Wiley Periodicals, Inc.

  10. Transcriptional and phenotypic changes in aorta and aortic valve with aging and MnSOD deficiency in mice

    PubMed Central

    Roos, Carolyn M.; Hagler, Michael; Zhang, Bin; Oehler, Elise A.; Arghami, Arman

    2013-01-01

    The purpose of this study was to characterize changes in antioxidant and age-related gene expression in aorta and aortic valve with aging, and test the hypothesis that increased mitochondrial oxidative stress accelerates age-related endothelial and aortic valve dysfunction. Wild-type (MnSOD+/+) and manganese SOD heterozygous haploinsufficient (MnSOD+/−) mice were studied at 3 and 18 mo of age. In aorta from wild-type mice, antioxidant expression was preserved, although there were age-associated increases in Nox2 expression. Haploinsufficiency of MnSOD did not alter antioxidant expression in aorta, but increased expression of Nox2. When compared with that of aorta, age-associated reductions in antioxidant expression were larger in aortic valves from wild-type and MnSOD haploinsufficient mice, although Nox2 expression was unchanged. Similarly, sirtuin expression was relatively well-preserved in aorta from both genotypes, whereas expression of SIRT1, SIRT2, SIRT3, SIRT4, and SIRT6 were significantly reduced in the aortic valve. Expression of p16ink4a, a marker of cellular senescence, was profoundly increased in both aorta and aortic valve from MnSOD+/+ and MnSOD+/− mice. Functionally, we observed comparable age-associated reductions in endothelial function in aorta from both MnSOD+/+ and MnSOD+/− mice. Interestingly, inhibition of NAD(P)H oxidase with apocynin or gp91ds-tat improved endothelial function in MnSOD+/+ mice but significantly impaired endothelial function in MnSOD+/− mice at both ages. Aortic valve function was not impaired by aging or MnSOD haploinsufficiency. Changes in antioxidant and sirtuin gene expression with aging differ dramatically between aorta and aortic valve. Furthermore, although MnSOD does not result in overt cardiovascular dysfunction with aging, compensatory transcriptional responses to MnSOD deficiency appear to be tissue specific. PMID:23997094

  11. Accelerated renal disease is associated with the development of metabolic syndrome in a glucolipotoxic mouse model

    PubMed Central

    Martínez-García, Cristina; Izquierdo, Adriana; Velagapudi, Vidya; Vivas, Yurena; Velasco, Ismael; Campbell, Mark; Burling, Keith; Cava, Fernando; Ros, Manuel; Orešič, Matej; Vidal-Puig, Antonio; Medina-Gomez, Gema

    2012-01-01

    SUMMARY Individuals with metabolic syndrome are at high risk of developing chronic kidney disease (CKD) through unclear pathogenic mechanisms. Obesity and diabetes are known to induce glucolipotoxic effects in metabolically relevant organs. However, the pathogenic role of glucolipotoxicity in the aetiology of diabetic nephropathy is debated. We generated a murine model, the POKO mouse, obtained by crossing the peroxisome proliferator-activated receptor gamma 2 (PPARγ2) knockout (KO) mouse into a genetically obese ob/ob background. We have previously shown that the POKO mice showed: hyperphagia, insulin resistance, hyperglycaemia and dyslipidaemia as early as 4 weeks of age, and developed a complete loss of normal β-cell function by 16 weeks of age. Metabolic phenotyping of the POKO model has led to investigation of the structural and functional changes in the kidney and changes in blood pressure in these mice. Here we demonstrate that the POKO mouse is a model of renal disease that is accelerated by high levels of glucose and lipid accumulation. Similar to ob/ob mice, at 4 weeks of age these animals exhibited an increased urinary albumin:creatinine ratio and significantly increased blood pressure, but in contrast showed a significant increase in the renal hypertrophy index and an associated increase in p27Kip1 expression compared with their obese littermates. Moreover, at 4 weeks of age POKO mice showed insulin resistance, an alteration of lipid metabolism and glomeruli damage associated with increased transforming growth factor beta (TGFβ) and parathyroid hormone-related protein (PTHrP) expression. At this age, levels of proinflammatory molecules, such as monocyte chemoattractant protein-1 (MCP-1), and fibrotic factors were also increased at the glomerular level compared with levels in ob/ob mice. At 12 weeks of age, renal damage was fully established. These data suggest an accelerated lesion through glucolipotoxic effects in the renal pathogenesis in POKO mice

  12. Accelerated renal disease is associated with the development of metabolic syndrome in a glucolipotoxic mouse model.

    PubMed

    Martínez-García, Cristina; Izquierdo, Adriana; Velagapudi, Vidya; Vivas, Yurena; Velasco, Ismael; Campbell, Mark; Burling, Keith; Cava, Fernando; Ros, Manuel; Oresic, Matej; Vidal-Puig, Antonio; Medina-Gomez, Gema

    2012-09-01

    Individuals with metabolic syndrome are at high risk of developing chronic kidney disease (CKD) through unclear pathogenic mechanisms. Obesity and diabetes are known to induce glucolipotoxic effects in metabolically relevant organs. However, the pathogenic role of glucolipotoxicity in the aetiology of diabetic nephropathy is debated. We generated a murine model, the POKO mouse, obtained by crossing the peroxisome proliferator-activated receptor gamma 2 (PPARγ2) knockout (KO) mouse into a genetically obese ob/ob background. We have previously shown that the POKO mice showed: hyperphagia, insulin resistance, hyperglycaemia and dyslipidaemia as early as 4 weeks of age, and developed a complete loss of normal β-cell function by 16 weeks of age. Metabolic phenotyping of the POKO model has led to investigation of the structural and functional changes in the kidney and changes in blood pressure in these mice. Here we demonstrate that the POKO mouse is a model of renal disease that is accelerated by high levels of glucose and lipid accumulation. Similar to ob/ob mice, at 4 weeks of age these animals exhibited an increased urinary albumin:creatinine ratio and significantly increased blood pressure, but in contrast showed a significant increase in the renal hypertrophy index and an associated increase in p27(Kip1) expression compared with their obese littermates. Moreover, at 4 weeks of age POKO mice showed insulin resistance, an alteration of lipid metabolism and glomeruli damage associated with increased transforming growth factor beta (TGFβ) and parathyroid hormone-related protein (PTHrP) expression. At this age, levels of proinflammatory molecules, such as monocyte chemoattractant protein-1 (MCP-1), and fibrotic factors were also increased at the glomerular level compared with levels in ob/ob mice. At 12 weeks of age, renal damage was fully established. These data suggest an accelerated lesion through glucolipotoxic effects in the renal pathogenesis in POKO mice.

  13. Development of a lifetime prediction model for lithium-ion batteries based on extended accelerated aging test data

    NASA Astrophysics Data System (ADS)

    Ecker, Madeleine; Gerschler, Jochen B.; Vogel, Jan; Käbitz, Stefan; Hust, Friedrich; Dechent, Philipp; Sauer, Dirk Uwe

    2012-10-01

    Battery lifetime prognosis is a key requirement for successful market introduction of electric and hybrid vehicles. This work aims at the development of a lifetime prediction approach based on an aging model for lithium-ion batteries. A multivariable analysis of a detailed series of accelerated lifetime experiments representing typical operating conditions in hybrid electric vehicle is presented. The impact of temperature and state of charge on impedance rise and capacity loss is quantified. The investigations are based on a high-power NMC/graphite lithium-ion battery with good cycle lifetime. The resulting mathematical functions are physically motivated by the occurring aging effects and are used for the parameterization of a semi-empirical aging model. An impedance-based electric-thermal model is coupled to the aging model to simulate the dynamic interaction between aging of the battery and the thermal as well as electric behavior. Based on these models different drive cycles and management strategies can be analyzed with regard to their impact on lifetime. It is an important tool for vehicle designers and for the implementation of business models. A key contribution of the paper is the parameterization of the aging model by experimental data, while aging simulation in the literature usually lacks a robust empirical foundation.

  14. Theory of Mind Indexes the Broader Autism Phenotype in Siblings of Children with Autism at School Age.

    PubMed

    Tsang, Tawny; Gillespie-Lynch, Kristen; Hutman, Ted

    2016-01-01

    Subclinical variants of the social-communicative challenges and rigidity that define autism spectrum disorder (ASD) are known as the broader autism phenotype (BAP). The BAP has been conceptualized categorically (as specific to a subset of relatives of individuals with ASD) and dimensionally (as continuously distributed within the general population). The current study examined the compatibility of these two approaches by assessing associations among autism symptoms and social-communicative skills in young school-age children with ASD, children who have a sibling with ASD, and children without a sibling with ASD. Autism symptoms were associated with reduced Theory of Mind (ToM), adaptive skills, cognitive empathy, and language skills across the full sample. Reduced ToM was a core aspect of the BAP in the current sample regardless of whether the BAP was defined categorically (in terms of siblings of children with ASD who exhibited atypical developmental) or dimensionally (in terms of associations with autism symptoms across the entire sample). Early language skills predicted school-age ToM. Findings support the compatibility of categorical and dimensional approaches to the BAP, highlight reduced ToM as a core aspect of the school-age BAP, and suggest that narrative-based approaches to promoting ToM may be beneficial for siblings of children with ASD.

  15. Epithelial phenotype and the RPE: Is the answer blowing in the Wnt?

    PubMed Central

    Burke, Janice M.

    2008-01-01

    Cells of the human retinal pigment epithelium (RPE) have a regular epithelial cell shape within the tissue in situ, but for reasons that remain elusive the RPE shows an incomplete and variable ability to re-develop an epithelial phenotype after propagation in vitro. In other epithelial cell cultures, formation of an adherens junction (AJ) composed of E-cadherin plays an important early inductive role in epithelial morphogenesis, but E-cadherin is largely absent from the RPE. In this review, the contribution of cadherins, both minor (E-cadherin) and major (N-cadherin), to RPE phenotype development is discussed. Emphasis is placed on the importance for future studies of actin cytoskeletal remodeling during assembly of the AJ, which in epithelial cells results in an actin organization that is characteristically zonular. Other markers of RPE phenotype that are used to gauge the maturation state of RPE cultures including tissue-specific protein expression, protein polarity, and pigmentation are described. An argument is made that RPE epithelial phenotype, cadherin-based cell–cell adhesion and melanization are linked by a common signaling pathway: the Wnt/β-catenin pathway. Analyzing this pathway and its intersecting signaling networks is suggested as a useful framework for dissecting the steps in RPE morphogenesis. Also discussed is the effect of aging on RPE phenotype. Preliminary evidence is provided to suggest that light-induced sub-lethal oxidative stress to cultured ARPE-19 cells impairs organelle motility. Organelle translocation, which is mediated by stress-susceptible cytoskeletal scaffolds, is an essential process in cell phenotype development and retention. The observation of impaired organelle motility therefore raises the possibility that low levels of stress, which are believed to accompany RPE aging, may produce subtle disruptions of cell phenotype. Over time these would be expected to diminish the support functions performed by the RPE on behalf of

  16. The association of ACE, ACTN3 and PPARA gene variants with strength phenotypes in middle school-age children.

    PubMed

    Ahmetov, Ildus I; Gavrilov, Dmitry N; Astratenkova, Irina V; Druzhevskaya, Anastasiya M; Malinin, Alexandr V; Romanova, Elena E; Rogozkin, Victor A

    2013-01-01

    The aim of the study was to determine the association between ACE I/D, ACTN3 R577X and PPARA intron 7 G/C gene polymorphisms and strength-related traits in 457 middle school-age children (219 boys and 238 girls; aged 11 ± 0.4 years). The assessment of different phenotypes was conducted with a number of performance tests. Gene polymorphisms were determined by PCR. The ACE D allele was associated with high results of standing long-jump test in boys [II 148.3 (16.3) cm, ID 152.6 (19.6) cm, DD 158.2 (19.1) cm; P = 0.037]. The ACTN3 R allele was associated with high results of performance tests in males only in combination with other genes (standing long-jump test: P = 0.021; handgrip strength test: P < 0.0001). Furthermore, the male carriers of the PPARA gene C allele demonstrated the best results of handgrip strength testing than GG homozygotes [GG 14.6 (4.0) kg, GC/CC 15.7 (4.3) kg; P = 0.048]. Thus, the ACE, ACTN3 and PPARA gene variants are associated with strength-related traits in physically active middle school-age boys.

  17. Rare diseases, rare presentations: recognizing atypical inherited kidney disease phenotypes in the age of genomics.

    PubMed

    Ars, Elisabet; Torra, Roser

    2017-10-01

    A significant percentage of adults (10%) and children (20%) on renal replacement therapy have an inherited kidney disease (IKD). The new genomic era, ushered in by the next generation sequencing techniques, has contributed to the identification of new genes and facilitated the genetic diagnosis of the highly heterogeneous IKDs. Consequently, it has also allowed the reclassification of diseases and has broadened the phenotypic spectrum of many classical IKDs. Various genetic, epigenetic and environmental factors may explain 'atypical' phenotypes. In this article, we examine different mechanisms that may contribute to phenotypic variability and also provide case examples that illustrate them. The aim of the article is to raise awareness, among nephrologists and geneticists, of rare presentations that IKDs may show, to facilitate diagnosis.

  18. Shade avoidance components and pathways in adult plants revealed by phenotypic profiling.

    PubMed

    Nozue, Kazunari; Tat, An V; Kumar Devisetty, Upendra; Robinson, Matthew; Mumbach, Maxwell R; Ichihashi, Yasunori; Lekkala, Saradadevi; Maloof, Julin N

    2015-04-01

    Shade from neighboring plants limits light for photosynthesis; as a consequence, plants have a variety of strategies to avoid canopy shade and compete with their neighbors for light. Collectively the response to foliar shade is called the shade avoidance syndrome (SAS). The SAS includes elongation of a variety of organs, acceleration of flowering time, and additional physiological responses, which are seen throughout the plant life cycle. However, current mechanistic knowledge is mainly limited to shade-induced elongation of seedlings. Here we use phenotypic profiling of seedling, leaf, and flowering time traits to untangle complex SAS networks. We used over-representation analysis (ORA) of shade-responsive genes, combined with previous annotation, to logically select 59 known and candidate novel mutants for phenotyping. Our analysis reveals shared and separate pathways for each shade avoidance response. In particular, auxin pathway components were required for shade avoidance responses in hypocotyl, petiole, and flowering time, whereas jasmonic acid pathway components were only required for petiole and flowering time responses. Our phenotypic profiling allowed discovery of seventeen novel shade avoidance mutants. Our results demonstrate that logical selection of mutants increased success of phenotypic profiling to dissect complex traits and discover novel components.

  19. Expression of CGRP neurotransmitter and vascular genesis marker mRNA is age-dependent in superior cervical ganglia of senescence-accelerated prone mice.

    PubMed

    Mitsuoka, Kazuyuki; Kikutani, Takeshi; Miwa, Yoko; Sato, Iwao

    2018-01-18

    Calcitonin gene-related peptide (CGRP) is a neurotransmitter that is released from the superior cervical ganglion (SCG) and causes head and neck pain. The morphological properties of human SCG neurons, including neurotransmitter content, are altered during aging. However, morphological changes in CGRP in the SCG during aging are not known. Therefore, we investigated CGRP and other markers in the SCG during aging in an aging model of senescence-accelerated prone mouse (SAMP8) and senescence-accelerated resistant mice (SAMR1) using real-time RT-PCR mRNA analyses and in situ hybridization. The abundance of neurotransmitter (CGRP, NPY, TRPV1), vascular genesis marker (CD31, LYVE-1), and cytochrome C mRNA differed between 12-week-old and 24-week-old SAMP8 and SAMR1. Abundance of TRPV1, CD31 and cytochrome C mRNAs of SAMP8 decreased between 12- and 24-week-old. The ratio of CGRP mRNA positive cells and CGRP mRNA abundance levels of the SCG of aging mouse such as SAMP8 have already been also higher than that of SAMR1 at 12-week-old. The CGRP positive shrunken ganglion cells was increased from 12- to 24-weeks-old mouse in SAMR1 and SAMP8. The SCG primarily affected the internal and external carotid arteries, larynx thyroid gland, and pharyngeal muscle during aging. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Cardiac remodelling in a baboon model of intrauterine growth restriction mimics accelerated ageing.

    PubMed

    Kuo, Anderson H; Li, Cun; Li, Jinqi; Huber, Hillary F; Nathanielsz, Peter W; Clarke, Geoffrey D

    2017-02-15

    Rodent models of intrauterine growth restriction (IUGR) successfully identify mechanisms that can lead to short-term and long-term detrimental cardiomyopathies but differences between rodent and human cardiac physiology and placental-fetal development indicate a need for models in precocial species for translation to human development. We developed a baboon model for IUGR studies using a moderate 30% global calorie restriction of pregnant mothers and used cardiac magnetic resonance imaging to evaluate offspring heart function in early adulthood. Impaired diastolic and systolic cardiac function was observed in IUGR offspring with differences between male and female subjects, compared to their respective controls. Aspects of cardiac impairment found in the IUGR offspring were similar to those found in normal controls in a geriatric cohort. Understanding early cardiac biomarkers of IUGR using non-invasive imaging in this susceptible population, especially taking into account sexual dimorphisms, will aid recognition of the clinical presentation, development of biomarkers suitable for use in humans and management of treatment strategies. Extensive rodent studies have shown that reduced perinatal nutrition programmes chronic cardiovascular disease. To enable translation to humans, we developed baboon offspring cohorts from mothers fed ad libitum (control) or 70% of the control ad libitum diet in pregnancy and lactation, which were growth restricted at birth. We hypothesized that intrauterine growth restriction (IUGR) offspring hearts would show impaired function and a premature ageing phenotype. We studied IUGR baboons (8 male, 8 female, 5.7 years), control offspring (8 male, 8 female, 5.6 years - human equivalent approximately 25 years), and normal elderly (OLD) baboons (6 male, 6 female, mean 15.9 years). Left ventricular (LV) morphology and systolic and diastolic function were evaluated with cardiac MRI and normalized to body surface area. Two-way ANOVA by group

  1. Social-emotional characteristics of gifted accelerated and non-accelerated students in the Netherlands.

    PubMed

    Hoogeveen, Lianne; van Hell, Janet G; Verhoeven, Ludo

    2012-12-01

    In the studies of acceleration conducted so far a multidimensional perspective has largely been neglected. No attempt has been made to relate social-emotional characteristics of accelerated versus non-accelerated students in perspective of environmental factors. In this study, social-emotional characteristics of accelerated gifted students in the Netherlands were examined in relation to personal and environmental factors. Self-concept and social contacts of accelerated (n = 148) and non-accelerated (n = 55) gifted students, aged 4 to 27 (M = 11.22, SD = 4.27) were measured. Self-concept and social contacts of accelerated and non-accelerated gifted students were measured using a questionnaire and a diary, and parents of these students evaluated their behavioural characteristics. Gender and birth order were studied as personal factors and grade, classroom, teachers' gender, teaching experience, and the quality of parent-school contact as environmental factors. The results showed minimal differences in the social-emotional characteristics of accelerated and non-accelerated gifted students. The few differences we found favoured the accelerated students. We also found that multiple grade skipping does not have negative effects on social-emotional characteristics, and that long-term effects of acceleration tend to be positive. As regards the possible modulation of personal and environmental factors, we merely found an impact of such factors in the non-accelerated group. The results of this study strongly suggest that social-emotional characteristics of accelerated gifted students and non-accelerated gifted students are largely similar. These results thus do not support worries expressed by teachers about the acceleration of gifted students. Our findings parallel the outcomes of earlier studies in the United States and Germany in that we observed that acceleration does not harm gifted students, not even in the case of multiple grade skipping. On the contrary, there is a

  2. GeneYenta: a phenotype-based rare disease case matching tool based on online dating algorithms for the acceleration of exome interpretation.

    PubMed

    Gottlieb, Michael M; Arenillas, David J; Maithripala, Savanie; Maurer, Zachary D; Tarailo Graovac, Maja; Armstrong, Linlea; Patel, Millan; van Karnebeek, Clara; Wasserman, Wyeth W

    2015-04-01

    Advances in next-generation sequencing (NGS) technologies have helped reveal causal variants for genetic diseases. In order to establish causality, it is often necessary to compare genomes of unrelated individuals with similar disease phenotypes to identify common disrupted genes. When working with cases of rare genetic disorders, finding similar individuals can be extremely difficult. We introduce a web tool, GeneYenta, which facilitates the matchmaking process, allowing clinicians to coordinate detailed comparisons for phenotypically similar cases. Importantly, the system is focused on phenotype annotation, with explicit limitations on highly confidential data that create barriers to participation. The procedure for matching of patient phenotypes, inspired by online dating services, uses an ontology-based semantic case matching algorithm with attribute weighting. We evaluate the capacity of the system using a curated reference data set and 19 clinician entered cases comparing four matching algorithms. We find that the inclusion of clinician weights can augment phenotype matching. © 2015 WILEY PERIODICALS, INC.

  3. Perturbations in growth trajectory due to early diet affect age-related deterioration in performance.

    PubMed

    Lee, Who-Seung; Monaghan, Pat; Metcalfe, Neil B

    2016-04-01

    Fluctuations in early developmental conditions can cause changes in growth trajectories that subsequently affect the adult phenotype. Here, we investigated whether compensatory growth has long-term consequences for patterns of senescence.Using three-spined sticklebacks ( Gasterosteus aculeatus ), we show that a brief period of dietary manipulation in early life affected skeletal growth rate not only during the manipulation itself, but also during a subsequent compensatory phase when fish caught up in size with controls.However, this growth acceleration influenced swimming endurance and its decline over the course of the breeding season, with a faster decline in fish that had undergone faster growth compensation.Similarly, accelerated growth led to a more pronounced reduction in the breeding period (as indicated by the duration of sexual ornamentation) over the following two breeding seasons, suggesting faster reproductive senescence. Parallel experiments showed a heightened effect of accelerated growth on these age-related declines in performance if the fish were under greater time stress to complete their compensation prior to the breeding season.Compensatory growth led to a reduction in median life span of 12% compared to steadily growing controls. While life span was independent of the eventual adult size attained, it was negatively correlated with the age-related decline in swimming endurance and sexual ornamentation.These results, complementary to those found when growth trajectories were altered by temperature rather than dietary manipulations, show that the costs of accelerated growth can last well beyond the time over which growth rates differ and are affected by the time available until an approaching life-history event such as reproduction.

  4. Soiling of building envelope surfaces and its effect on solar reflectance – Part II: Development of an accelerated aging method for roofing materials

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Sleiman, Mohamad; Kirchstetter, Thomas W.; Berdahl, Paul

    2014-01-09

    Highly reflective roofs can decrease the energy required for building air conditioning, help mitigate the urban heat island effect, and slow global warming. However, these benefits are diminished by soiling and weathering processes that reduce the solar reflectance of most roofing materials. Soiling results from the deposition of atmospheric particulate matter and the growth of microorganisms, each of which absorb sunlight. Weathering of materials occurs with exposure to water, sunlight, and high temperatures. This study developed an accelerated aging method that incorporates features of soiling and weathering. The method sprays a calibrated aqueous soiling mixture of dust minerals, black carbon,more » humic acid, and salts onto preconditioned coupons of roofing materials, then subjects the soiled coupons to cycles of ultraviolet radiation, heat and water in a commercial weatherometer. Three soiling mixtures were optimized to reproduce the site-specific solar spectral reflectance features of roofing products exposed for 3 years in a hot and humid climate (Miami, Florida); a hot and dry climate (Phoenix, Arizona); and a polluted atmosphere in a temperate climate (Cleveland, Ohio). A fourth mixture was designed to reproduce the three-site average values of solar reflectance and thermal emittance attained after 3 years of natural exposure, which the Cool Roof Rating Council (CRRC) uses to rate roofing products sold in the US. This accelerated aging method was applied to 25 products₋single ply membranes, factory and field applied coatings, tiles, modified bitumen cap sheets, and asphalt shingles₋and reproduced in 3 days the CRRC's 3-year aged values of solar reflectance. In conclusion, this accelerated aging method can be used to speed the evaluation and rating of new cool roofing materials.« less

  5. The Influence of Passive Acceleration and Exercise+Acceleration on Work Capacity and Orthostasis

    NASA Technical Reports Server (NTRS)

    Simonson, S. R.; Cowell, S. A.; Stocks, J. M.; Biagini, H. W.; Vener, J. M.; Evetts, S. N.; Bailey, K. N.; Evans, J.; Knapp, C.; Greenleaf, J. E.

    1999-01-01

    The losses of aerobic power and orthostatic tolerance are significant effects of manned C) spaceflight that can negatively impact crew health and safety. Daily acceleration and aerobic training may ameliorate these effects. To determine the influence of passive intermittent +Gz acceleration (PA) training and active acceleration + interval exercise (AE) training on work 0 0 capacity and the acute (1 min) response to 70 deg head-up tilt, 6 men (X-Bar SD: age, 33 +/- 6 y; height, 178.3 +/- 4.6 cm; mass, 86.3 +/- 6.6 kg) participated in two 3-wk training protocols. It was hypothesized that PA and AE training would improve orthostatic tolerance and that the addition of aerobic conditioning, would not alter this effect.

  6. The NKI-Rockland Sample: A Model for Accelerating the Pace of Discovery Science in Psychiatry

    PubMed Central

    Nooner, Kate Brody; Colcombe, Stanley J.; Tobe, Russell H.; Mennes, Maarten; Benedict, Melissa M.; Moreno, Alexis L.; Panek, Laura J.; Brown, Shaquanna; Zavitz, Stephen T.; Li, Qingyang; Sikka, Sharad; Gutman, David; Bangaru, Saroja; Schlachter, Rochelle Tziona; Kamiel, Stephanie M.; Anwar, Ayesha R.; Hinz, Caitlin M.; Kaplan, Michelle S.; Rachlin, Anna B.; Adelsberg, Samantha; Cheung, Brian; Khanuja, Ranjit; Yan, Chaogan; Craddock, Cameron C.; Calhoun, Vincent; Courtney, William; King, Margaret; Wood, Dylan; Cox, Christine L.; Kelly, A. M. Clare; Di Martino, Adriana; Petkova, Eva; Reiss, Philip T.; Duan, Nancy; Thomsen, Dawn; Biswal, Bharat; Coffey, Barbara; Hoptman, Matthew J.; Javitt, Daniel C.; Pomara, Nunzio; Sidtis, John J.; Koplewicz, Harold S.; Castellanos, Francisco Xavier; Leventhal, Bennett L.; Milham, Michael P.

    2012-01-01

    The National Institute of Mental Health strategic plan for advancing psychiatric neuroscience calls for an acceleration of discovery and the delineation of developmental trajectories for risk and resilience across the lifespan. To attain these objectives, sufficiently powered datasets with broad and deep phenotypic characterization, state-of-the-art neuroimaging, and genetic samples must be generated and made openly available to the scientific community. The enhanced Nathan Kline Institute-Rockland Sample (NKI-RS) is a response to this need. NKI-RS is an ongoing, institutionally centered endeavor aimed at creating a large-scale (N > 1000), deeply phenotyped, community-ascertained, lifespan sample (ages 6–85 years old) with advanced neuroimaging and genetics. These data will be publically shared, openly, and prospectively (i.e., on a weekly basis). Herein, we describe the conceptual basis of the NKI-RS, including study design, sampling considerations, and steps to synchronize phenotypic and neuroimaging assessment. Additionally, we describe our process for sharing the data with the scientific community while protecting participant confidentiality, maintaining an adequate database, and certifying data integrity. The pilot phase of the NKI-RS, including challenges in recruiting, characterizing, imaging, and sharing data, is discussed while also explaining how this experience informed the final design of the enhanced NKI-RS. It is our hope that familiarity with the conceptual underpinnings of the enhanced NKI-RS will facilitate harmonization with future data collection efforts aimed at advancing psychiatric neuroscience and nosology. PMID:23087608

  7. Accelerated Testing Of Photothermal Degradation Of Polymers

    NASA Technical Reports Server (NTRS)

    Kim, Soon Sam; Liang, Ranty Hing; Tsay, Fun-Dow

    1989-01-01

    Electron-spin-resonance (ESR) spectroscopy and Arrhenius plots used to determine maximum safe temperature for accelerated testing of photothermal degradation of polymers. Aging accelerated by increasing illumination, temperature, or both. Results of aging tests at temperatures higher than those encountered in normal use valid as long as mechanism of degradation same throughout range of temperatures. Transition between different mechanisms at some temperature identified via transition between activation energies, manifesting itself as change in slope of Arrhenius plot at that temperature.

  8. Accelerated aging tests on ENEA-ASE solar coating for receiver tube suitable to operate up to 550 °C

    NASA Astrophysics Data System (ADS)

    Antonaia, A.; D'Angelo, A.; Esposito, S.; Addonizio, M. L.; Castaldo, A.; Ferrara, M.; Guglielmo, A.; Maccari, A.

    2016-05-01

    A patented solar coating for evacuated receiver, based on innovative graded WN-AlN cermet layer, has been optically designed and optimized to operate at high temperature with high performance and high thermal stability. This solar coating, being designed to operate in solar field with molten salt as heat transfer fluid, has to be thermally stable up to the maximum temperature of 550 °C. With the aim of determining degradation behaviour and lifetime prediction of the solar coating, we chose to monitor the variation of the solar absorptance αs after each thermal annealing cycle carried out at accelerated temperatures under vacuum. This prediction method was coupled with a preliminary Differential Thermal Analysis (DTA) in order to give evidence for any chemical-physical coating modification in the temperature range of interest before performing accelerated aging tests. In the accelerated aging tests we assumed that the temperature dependence of the degradation processes could be described by Arrhenius behaviour and we hypothesized that a linear correlation occurs between optical parameter variation rate (specifically, Δαs/Δt) and degradation process rate. Starting from Δαs/Δt values evaluated at 650 and 690 °C, Arrhenius plot gave an activation energy of 325 kJ mol-1 for the degradation phenomenon, where the prediction on the coating degradation gave a solar absorptance decrease of only 1.65 % after 25 years at 550 °C. This very low αs decrease gave evidence for an excellent stability of our solar coating, also when employed at the maximum temperature (550 °C) of a solar field operating with molten salt as heat transfer fluid.

  9. Genetic and Diagnostic Biomarker Development in ASD Toddlers Using Resting State Functional MRI

    DTIC Science & Technology

    2017-11-01

    Integration Theory of intelligence (Jung and Haier, Behave Brain Sci, 2007...predicting a number of age-related phenotypes. Measures of white matter integrity in the brain are heritable and highly sensitive to both normal and...pathological aging processes. We consider the phenotypic and genetic interrelationships between epigenetic age acceleration and white matter integrity

  10. Polymorphisms of CYP1A2 and CYP2A6 activity: phenotypes and the effect of age and sex in a Nigerian population.

    PubMed

    Adehin, Ayorinde; Bolaji, Oluseye O

    2015-09-01

    CYP1A2 and CYP2A6 are polymorphic enzymes that metabolise several compounds of clinical importance. This study investigated the prevalent phenotypes of these enzymes and the influence of age and sex on enzyme activity in a Nigerian population. Caffeine (110 mg) was administered to each of 129 healthy, unrelated subjects (85 males and 44 females) who were non-smokers. Urine voided within 7 h after caffeine administration was collected for a high performance liquid chromatographic assay of caffeine (137X), 1,7-dimethyluric acid (17U) and 1,7-dimethylxanthine (17X). CYP1A2 activity was measured as a ratio of (17U+17X) to 137X, while 17U/17X served as marker for CYP2A6. Transformed data were analysed and the influences of age and sex on activity were also determined. Distribution of CYP1A2 activity in the population was bimodal with a mean±SD of 0.82±0.41, while that of CYP2A6 was trimodal with a mean±SD activity of 0.27±0.42 of the log-transformed urinary molar ratio of metabolites. The influences of age and sex on enzyme activity for both CYP1A2 and CYP2A6 were not significant (p>0.05). The study established the prevalence of polymorphism in phenotypes of CYP1A2 and CYP2A6 activity in the Nigerian population, but no influence of age and sex on enzyme activity was observed in this population.

  11. Accelerated Aging Experiments for Prognostics of Damage Growth in Composite Materials

    NASA Technical Reports Server (NTRS)

    Saxena, Abhinav; Goebel, Kai Frank; Larrosa, Cecilia C.; Janapati, Vishnuvardhan; Roy, Surajit; Chang, Fu-Kuo

    2011-01-01

    Composite structures are gaining importance for use in the aerospace industry. Compared to metallic structures their behavior is less well understood. This lack of understanding may pose constraints on their use. One possible way to deal with some of the risks associated with potential failure is to perform in-situ monitoring to detect precursors of failures. Prognostic algorithms can be used to predict impending failures. They require large amounts of training data to build and tune damage model for making useful predictions. One of the key aspects is to get confirmatory feedback from data as damage progresses. These kinds of data are rarely available from actual systems. The next possible resource to collect such data is an accelerated aging platform. To that end this paper describes a fatigue cycling experiment with the goal to stress carbon-carbon composite coupons with various layups. Piezoelectric disc sensors were used to periodically interrogate the system. Analysis showed distinct differences in the signatures of growing failures between data collected at conditions. Periodic X-radiographs were taken to assess the damage ground truth. Results after signal processing showed clear trends of damage growth that were correlated to damage assessed from the X-ray images.

  12. The schedule of administration of canakinumab in cryopyrin associated periodic syndrome is driven by the phenotype severity rather than the age

    PubMed Central

    2013-01-01

    Introduction Interleukin-1 (IL-1) blockade is the treatment of choice of cryopyrin associated periodic syndromes (CAPS). Anti-IL-1 monoclonal antibody (canakinumab) was recently registered. However no clear data are available on the optimal schedule of administration of this drug. The aim of the present study was to analyse the impact of canakinumab on CAPS patients in daily clinical practice and to identify the best schedule of administration according to age and phenotype. Methods 13 CAPS patients (10 children and 3 young adults) treated with canakinumab were followed for 12 months. Clinical and laboratory parameters were collected at each visit. Health-related quality of life (HRQoL) was recorded at month 12. Complete response was defined as absence of clinical manifestations and normal examinations. Clinical and laboratory variables at last follow-up were compared with those registered at the moment of anakinra discontinuation. Results seven patients with chronic infantile neurological cutaneous articular (CINCA) syndrome, four patients with Muckle-Wells syndrome (MWS) and two patients with an overlapping MWS/CINCA phenotype were analysed. CINCA patients experienced a higher number of modifications of the treatment (increased dosage or decreased dosing interval) in respect to MWS patients. At the end of the follow-up CINCA patients displayed a higher frequency of administration with a median dose of 3.7 mg/kg (2.1 mg/kg for MWS patients). Canakinumab was withdrawn in a patient with CINCA for incomplete response and poor compliance. The effect of canakinumab on HRQoL was similar to that observed during treatment with anakinra, with the exception of an improvement of the psychosocial concepts after the introduction of canakinumab. Conclusions The use of canakinumab in daily practice is associated with persistent satisfactory control of disease activity but needs progressive dose adjustments in more severe patients. The clinical phenotype, rather than the age

  13. [A paradox of a parasite prolonging the life of its host. Pearl mussel can cancel the accelerated aging program in salmon].

    PubMed

    Ziuganov, V V

    2005-01-01

    A unique case is analyzed when the accelerated aging program (progeria) in salmons (Salmonidae) can be canceled by larval parasite of the gills--freshwater pearl mussel Margaritifera margaritifera. As a result, the maximum age of Salmo fishes hosting the mussel can be as high as 13 years. The mollusk-fish system made it possible to demonstrate that the parasite can inhibit aging of the host and stimulate nonspecific resistance to stress, i.e., can control longevity. The mussel proved to increase the resistance to epitheliomata and cutaneous mycoses. The parasite is perceived to neutralize the senile changes in the regulatory system hypothalamus-pituitary-peripheral endocrine glands-hypothalamus of salmon.

  14. Phenotypic and Functional Characterization of Peripheral Blood Lymphocytes from Various Age- and Sex-Specific Groups of Owl Monkeys (Aotus nancymaae).

    PubMed

    Nehete, Pramod N; Nehete, Bharti P; Chitta, Sriram; Williams, Lawrence E; Abee, Christian R

    2017-02-01

    Owl monkeys (Aotus nancymaae) are New World NHP that serve an important role in vaccine development and as a model for human disease conditions such as malaria. Despite the past contributions of this animal model, limited information is available about the phenotype and functional properties of peripheral blood lymphocytes in reference to sex and age. Using a panel of human antibodies and a set of standardized human immune assays, we identified and characterized various peripheral blood lymphocyte subsets, evaluated the immune functions of T cells, and analyzed cytokines relative to sex and age in healthy owl monkeys. We noted age- and sex-dependent changes in CD28+ (an essential T cell costimulatory molecule) and CD95+ (an apoptotic surface marker) T cells and various levels of cytokines in the plasma. In immune assays of freshly isolated peripheral blood mononuclear cells, IFNγ and perforin responses were significantly higher in female than in male monkeys and in young adults than in juvenile and geriatric groups, despite similar lymphocyte (particularly T cell) populations in these groups. Our current findings may be useful in exploring Aotus monkeys as a model system for the study of aging, susceptibility to infectious diseases, and age-associated differences in vaccine efficacy, and other challenges particular to pediatric and geriatric patients.

  15. Age-Related Behavioral Phenotype of an Astrocytic Monoamine Oxidase-B Transgenic Mouse Model of Parkinson’s Disease

    PubMed Central

    Lieu, Christopher A.; Chinta, Shankar J.; Rane, Anand; Andersen, Julie K.

    2013-01-01

    We have previously shown that increases in astrocytic monoamine oxidase-B (MAO-B) expression, mimicking that which occurs with aging and in neurodegenerative disease, in a doxycycline (dox)-inducible transgenic mouse model evokes neuropathological similarities to what is observed in the human parkinsonian brain. Additional behavioral and neuropathological studies could provide further validation for its usage as a model for Parkinson’s disease (PD). In the present study, we utilized a battery of behavioral tests to evaluate age-related phenotype in this model. In the open field test, we found that dox-induction impaired motor ability with decreases in movement and ambulatory function as well as diminished stereotypical, repetitive movement episodes in both young and old mice. Older mice also showed decreased motor performance in the pole test when compared to younger mice. Furthermore, dox-induced older mice displayed severe hindlimb clasping and the most significant loss of dopamine (DA) in the striatum when compared to young and non-induced animals. Additionally, increased MAO-B activity significantly correlated with decreased expression of striatal DA. The results of our study further confirms that the dox-inducible astrocytic MAO-B transgenic mouse displays similar age-related behavioral and neuropathological features to other models of PD, and could serve as a useful tool to study PD pathophysiology and for the evaluation of therapeutic interventions. PMID:23326597

  16. Phenotypes and enviromental factors: their influence in PCOS.

    PubMed

    Diamanti-Kandarakis, Evanthia; Christakou, Charikleia; Marinakis, Evangelos

    2012-01-01

    Polycystic ovary syndrome (PCOS) is a complex syndrome of unclear etiopathogenesis characterized by heterogeneity in phenotypic manifestations. The clinical phenotype of PCOS includes reproductive and hormonal aberrations, namely anovulation and hyperandrogenism, which coexist with metabolic disturbances. Reflecting the crosstalk between the reproductive system and metabolic tissues, obesity not only deteriorates the metabolic profile but also aggravates ovulatory dysfunction and hyperandrogenism. Although the pathogenesis of PCOS remains unclear, the syndrome appears to involve environmental and genetic components. Starting from early life and extending throughout lifecycle, environmental insults may affect susceptible women who finally demonstrate the clinical phenotype of PCOS. Diet emerges as the major environmental determinant of PCOS. Overnutrition leading to obesity is widely recognized to have an aggravating impact, while another detrimental dietary factor may be the high content of food in advanced glycated end products (AGEs). Environmental exposure to industrial products, particularly Bisphenol A (BPA), may also exacerbate the clinical course of PCOS. AGEs and BPA may act as endocrine disruptors in the pathogenesis of the syndrome. PCOS appears to mirror the harmful influence of the modern environment on the reproductive and metabolic balance of inherently predisposed individuals.

  17. Psoriasis and polycystic ovary syndrome: a new link in different phenotypes.

    PubMed

    Moro, Francesca; Tropea, Anna; Scarinci, Elisa; Federico, Alex; De Simone, Clara; Caldarola, Giacomo; Leoncini, Emanuele; Boccia, Stefania; Lanzone, Antonio; Apa, Rosanna

    2015-08-01

    Women affected by PCOS and psoriasis are more likely to have insulin-resistance, hyperinsulinemia, reduced HDL cholesterol levels and a more severe degree of skin disease than those with psoriasis alone. The mechanism underlying this association between PCOS and psoriasis is currently unknown. The aim of the present study was to evaluate the features of psoriasis and the psoriasis severity scores in the different PCOS phenotypes and in age and body mass index (BMI)-matched psoriatic control patients. A cross-sectional study was performed on 150 psoriatic patients: 94 PCOS and 56 age- and BMI-matched controls. PCOS patients were diagnosed and divided into four phenotypes according to Rotterdam criteria: A - patients with complete phenotype with hyperandrogenism (H) plus oligoamenorrhea (O) plus polycystic ovary (PCO) on ultrasound examination; B - patients with H plus O (without PCO); C - patients with H plus PCO (ovulatory phenotype); D - patients with O plus PCO (without H). The patient's Psoriasis Area and Severity Index (PASI) as well as the Physician's Global Assessment (PGA) were calculated. A PASI score ≥10 was correlated with common indicator of severe disease. A PGA ≥4 was considered as a condition of moderate to severe disease. Among the four phenotypes investigated, the group with complete phenotype (H plus O plus PCO) had a higher prevalence of patients with patient's PASI ≥10 compared to controls (Odds Ratio (OR) 4.71, 95% confidence intervals (CI) 1.59-13.95). The group with O plus PCO had a higher prevalence of patients with PGA ≥4 compared to controls (OR 26.79, 95% CI 3.40-211.02) while the ovulatory group had a lower prevalence of patients with PGA ≥4 (OR 0.06, 95% CI 0.01-0.51). The ovulatory phenotype displays a milder psoriasis form than other phenotypes while the phenotypes with oligoamenorrhea presented higher severity scores of disease than other phenotypes and control group. Copyright © 2015 Elsevier Ireland Ltd. All rights

  18. Universality of accelerating change

    NASA Astrophysics Data System (ADS)

    Eliazar, Iddo; Shlesinger, Michael F.

    2018-03-01

    On large time scales the progress of human technology follows an exponential growth trend that is termed accelerating change. The exponential growth trend is commonly considered to be the amalgamated effect of consecutive technology revolutions - where the progress carried in by each technology revolution follows an S-curve, and where the aging of each technology revolution drives humanity to push for the next technology revolution. Thus, as a collective, mankind is the 'intelligent designer' of accelerating change. In this paper we establish that the exponential growth trend - and only this trend - emerges universally, on large time scales, from systems that combine together two elements: randomness and amalgamation. Hence, the universal generation of accelerating change can be attained by systems with no 'intelligent designer'.

  19. Absence of association of a single-nucleotide polymorphism in the TERT-CLPTM1L locus with age-related phenotypes in a large multicohort study: the HALCyon programme.

    PubMed

    Alfred, Tamuno; Ben-Shlomo, Yoav; Cooper, Rachel; Hardy, Rebecca; Cooper, Cyrus; Deary, Ian J; Elliott, Jane; Gunnell, David; Harris, Sarah E; Kivimaki, Mika; Kumari, Meena; Martin, Richard M; Power, Chris; Sayer, Avan Aihie; Starr, John M; Kuh, Diana; Day, Ian N M

    2011-06-01

    Several age-related traits are associated with shorter telomeres, the structures that cap the end of linear chromosomes. A common polymorphism near the telomere maintenance gene TERT has been associated with several cancers, but relationships with other aging traits such as physical capability have not been reported. As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, men and women aged between 44 and 90 years from nine UK cohorts were genotyped for the single-nucleotide polymorphism (SNP) rs401681. We then investigated relationships between the SNP and 30 age-related phenotypes, including cognitive and physical capability, blood lipid levels and lung function, pooling within-study genotypic effects in meta-analyses. No significant associations were found between the SNP and any of the cognitive performance tests (e.g. pooled beta per T allele for word recall z-score = 0.02, 95% CI: -0.01 to 0.04, P-value = 0.12, n = 18,737), physical performance tests (e.g. pooled beta for grip strength = -0.02, 95% CI: -0.045 to 0.006, P-value = 0.14, n = 11,711), blood pressure, lung function or blood test measures. Similarly, no differences in observations were found when considering follow-up measures of cognitive or physical performance after adjusting for its measure at an earlier assessment. The lack of associations between SNP rs401681 and a wide range of age-related phenotypes investigated in this large multicohort study suggests that while this SNP may be associated with cancer, it is not an important contributor to other markers of aging. © 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

  20. Factors in Early Adolescence Associated With a Mole-Prone Phenotype in Late Adolescence.

    PubMed

    Xu, Haoming; Marchetti, Michael A; Dusza, Stephen W; Chung, Esther; Fonseca, Maira; Scope, Alon; Geller, Alan C; Bishop, Marilyn; Marghoob, Ashfaq A; Halpern, Allan C

    2017-10-01

    Nevi are important phenotypic risk factors for melanoma in adults. Few studies have examined the constitutional and behavioral factors associated with a mole-prone phenotype in adolescents. To identify host, behavioral, and dermoscopic factors in early adolescence (age, 14 years) that are associated with a mole-prone phenotype in late adolescence (age, 17 years). A prospective observational cohort study from the Study of Nevi in Children was conducted from January 1, 2009, to December 31, 2014, with a 2- to 3-year follow-up. A total of 569 students from the school system in Framingham, Massachusetts, were enrolled in the 8th or 9th grade (baseline; mean [SD] age, 14.4 [0.7] years). The overall retention rate was 73.3%, and 417 students were reassessed in the 11th grade. Mole-prone phenotype in the 11th grade, defined as total nevus count of the back and 1 randomly selected leg in the top decile of the cohort or having any nevi greater than 5 mm in diameter. Of the 417 students assessed at follow-up in the 11th grade (166 females and 251 males; mean [SD] age, 17.0 [0.4] years), 111 participants (26.6%) demonstrated a mole-prone phenotype: 69 students (62.2%) with 1 nevus greater than 5 mm in diameter, 23 students (20.7%) with total nevus count in the top decile, and 19 students (17.1%) with both characteristics. On multivariate analysis, baseline total nevus count (adjusted odds ratio, 9.08; 95% CI, 4.0-23.7; P < .001) and increased variability of nevus dermoscopic pattern (adjusted odds ratio, 4.24; 95% CI, 1.36-13.25; P = .01) were associated with a mole-prone phenotype. This study found clinically recognizable factors associated with a mole-prone phenotype that may facilitate the identification of individuals at risk for melanoma. These findings could have implications for primary prevention strategies and help target at-risk adolescents for higher-intensity counseling about sun protection and skin self-examination.

  1. Disparity between online and offline tests in accelerated aging tests of LED lamps under electric stress.

    PubMed

    Wang, Yao; Jing, Lei; Ke, Hong-Liang; Hao, Jian; Gao, Qun; Wang, Xiao-Xun; Sun, Qiang; Xu, Zhi-Jun

    2016-09-20

    The accelerated aging tests under electric stress for one type of LED lamp are conducted, and the differences between online and offline tests of the degradation of luminous flux are studied in this paper. The transformation of the two test modes is achieved with an adjustable AC voltage stabilized power source. Experimental results show that the exponential fitting of the luminous flux degradation in online tests possesses a higher fitting degree for most lamps, and the degradation rate of the luminous flux by online tests is always lower than that by offline tests. Bayes estimation and Weibull distribution are used to calculate the failure probabilities under the accelerated voltages, and then the reliability of the lamps under rated voltage of 220 V is estimated by use of the inverse power law model. Results show that the relative error of the lifetime estimation by offline tests increases as the failure probability decreases, and it cannot be neglected when the failure probability is less than 1%. The relative errors of lifetime estimation are 7.9%, 5.8%, 4.2%, and 3.5%, at the failure probabilities of 0.1%, 1%, 5%, and 10%, respectively.

  2. Reduced mitochondrial SOD displays mortality characteristics reminiscent of natural aging

    PubMed Central

    Paul, Anirban; Belton, Amy; Nag, Sanjay; Martin, Ian; Grotewiel, Michael S.; Duttaroy, Atanu

    2009-01-01

    Manganese superoxide dismutase (MnSOD or SOD2) is a key mitochondrial enzymatic antioxidant. Arguably the most striking phenotype associated with complete loss of SOD2 in flies and mice is shortened life span. To further explore the role of SOD2 in protecting animals from aging and age-associated pathology, we generated a unique collection of Drosophila mutants that progressively reduce SOD2 expression and function. Mitochondrial aconitase activity was substantially reduced in the Sod2 mutants, suggesting that SOD2 normally ensures the functional capacity of mitochondria. Flies with severe reductions in SOD2 expression exhibited accelerated senescence of olfactory behavior as well as precocious neurodegeneration and DNA strand breakage in neurons. Furthermore, life span was progressively shortened and age-dependent mortality was increased in conjunction with reduced SOD2 expression, while initial mortality and developmental viability were unaffected. Interestingly, life span and age-dependent mortality varied exponentially with SOD2 activity, indicating that there might normally be a surplus of this enzyme for protecting animals from premature death. Our data support a model in which disruption of the protective effects of SOD2 on mitochondria manifests as profound changes in behavioral and demographic aging as well as exacerbated age-related pathology in the nervous system. PMID:18078670

  3. Mouse Tmem135 mutation reveals a mechanism involving mitochondrial dynamics that leads to age-dependent retinal pathologies

    PubMed Central

    Lee, Wei-Hua; Higuchi, Hitoshi; Ikeda, Sakae; Macke, Erica L; Takimoto, Tetsuya; Pattnaik, Bikash R; Liu, Che; Chu, Li-Fang; Siepka, Sandra M; Krentz, Kathleen J; Rubinstein, C Dustin; Kalejta, Robert F; Thomson, James A; Mullins, Robert F; Takahashi, Joseph S; Pinto, Lawrence H; Ikeda, Akihiro

    2016-01-01

    While the aging process is central to the pathogenesis of age-dependent diseases, it is poorly understood at the molecular level. We identified a mouse mutant with accelerated aging in the retina as well as pathologies observed in age-dependent retinal diseases, suggesting that the responsible gene regulates retinal aging, and its impairment results in age-dependent disease. We determined that a mutation in the transmembrane 135 (Tmem135) is responsible for these phenotypes. We observed localization of TMEM135 on mitochondria, and imbalance of mitochondrial fission and fusion in mutant Tmem135 as well as Tmem135 overexpressing cells, indicating that TMEM135 is involved in the regulation of mitochondrial dynamics. Additionally, mutant retina showed higher sensitivity to oxidative stress. These results suggest that the regulation of mitochondrial dynamics through TMEM135 is critical for protection from environmental stress and controlling the progression of retinal aging. Our study identified TMEM135 as a critical link between aging and age-dependent diseases. DOI: http://dx.doi.org/10.7554/eLife.19264.001 PMID:27863209

  4. Muscle-specific inositide phosphatase (MIP/MTMR14) is reduced with age and its loss accelerates skeletal muscle aging process by altering calcium homeostasis.

    PubMed

    Romero-Suarez, Sandra; Shen, Jinhua; Brotto, Leticia; Hall, Todd; Mo, Chenglin; Valdivia, Héctor H; Andresen, Jon; Wacker, Michael; Nosek, Thomas M; Qu, Cheng-Kui; Brotto, Marco

    2010-08-01

    We have recently reported that a novel muscle-specific inositide phosphatase (MIP/MTMR14) plays a critical role in [Ca2+]i homeostasis through dephosphorylation of sn-1-stearoyl-2-arachidonoyl phosphatidylinositol (3,5) bisphosphate (PI(3,5)P2). Loss of function mutations in MIP have been identified in human centronuclear myopathy. We developed a MIP knockout (MIPKO) animal model and found that MIPKO mice were more susceptible to exercise-induced muscle damage, a trademark of muscle functional changes in older subjects. We used wild-type (Wt) mice and MIPKO mice to elucidate the roles of MIP in muscle function during aging. We found MIP mRNA expression, MIP protein levels, and MIP phosphatase activity significantly decreased in old Wt mice. The mature MIPKO mice displayed phenotypes that closely resembled those seen in old Wt mice: i) decreased walking speed, ii) decreased treadmill activity, iii) decreased contractile force, and iv) decreased power generation, classical features of sarcopenia in rodents and humans. Defective Ca2+ homeostasis is also present in mature MIPKO and old Wt mice, suggesting a putative role of MIP in the decline of muscle function during aging. Our studies offer a new avenue for the investigation of MIP roles in skeletal muscle function and as a potential therapeutic target to treat aging sarcopenia.

  5. The mitochondrial and kidney disease phenotypes of kd/kd mice under germfree conditions

    PubMed Central

    Hallman, Troy M.; Peng, Min; Meade, Ray; Hancock, Wayne W.; Madaio, Michael P.; Gasser, David L.

    2008-01-01

    Interstitial nephritis occurs spontaneously in kd/kd mice, but the mechanisms leading to this disease have not been fully elucidated. The earliest manifestation of a phenotype is the appearance of ultrastructural defects in the mitochondria of mice as young as 42 days of age. To examine the influence of the environment on the phenotype, homozygous B6.kd/kd mice were transferred from specific pathogen-free (SPF) conditions to a germfree (GF) environment, and the development of the disease was observed. The GF state resulted in a highly significant reduction in the frequency of tubulointerstitial nephritis. In addition, GF conditions markedly reduced the appearance of the mitochondrial phenotype, with no sign of mitochondrial abnormalities in GF mice of up to 155 days of age. These results suggest that environmental factors are involved in the progression of all known manifestations of this disease phenotype. PMID:16337774

  6. Age- and Sex-associated Differences in Phenotypic and Functional Characteristics of Peripheral Blood Lymphocytes in Chimpanzees (Pan troglodytes).

    PubMed

    Nehete, Pramod N; Magden, Elizabeth R; Nehete, Bharti P; Williams, Lawrence E; Abee, Christian R; Sastry, K Jagannadha

    2017-09-01

    Chimpanzees are the closest phylogenetic relatives to humans, sharing more than 98% genetic sequence identity. These genetic similarities prompted the belief that chimpanzees can serve as an ideal model for human disease conditions and vaccine development. However, in light of the recent NIH decision to phase out biomedical research in chimpanzees and retire NIH-supported chimpanzees, data from the present study will continue to provide value for the care of aged and sick chimpanzees located in zoos, sanctuaries, and primate centers. Surprisingly little information has been published regarding the normal chimpanzee immune system, and most extant studies have been based on small numbers of animals. In the current study, we provide a better understanding of the chimpanzee immune system with regard to age and sex. We examined immune parameters of chimpanzees (n = 94; 51 female, 43 male; age, 6 to 47 y) by using flow cytometry, immune function analysis, and cytokine analysis. Because lymphocytes are key mediators of cellular immune responses, particularly to intracellular pathogens such as viruses, we surveyed the phenotypic and functional attributes of T and B lymphocytes in this healthy and age-stratified population of chimpanzees. We noted a significantly higher percentage of CD16+T cells in male compared with female chimpanzees but no significant changes in percentages of CD3+, CD4+, CD8+, or CD4+CD8+ T cells with age or sex. In addition, aging was associated with decreased proliferative responses to mitogens in both sexes. Sex-specific differences also were present in the percentage of NK cells but not in their cytotoxic activity and in circulating cytokine levels in plasma. Going forward, the data presented here regarding immune cell changes associated with aging in healthy chimpanzees will serve to enhance the care of geriatric and ill animals.

  7. 'Accelerated aging': a primrose path to insight?

    PubMed

    Miller, Richard A

    2004-04-01

    Organism envy afflicts most researchers who work on aging in mice; how frustrating it is to see the worm and fly biologists nail down milestone after milestone, citation after citation! Surely genetic trickery can produce mice that age in a comparable jiffy? Alas, our near-total ignorance of what times the aging process makes it hard to guess what genes to tweak, if indeed aging can be mimicked a presto. Building a case that a given short-lived mutant ages quickly is a steep and thorny path, requiring more than just plucking a symptom here and there from a list of things that sometimes go wrong in old people or old mice. The hallmark of aging is that a lot goes wrong more or less at the same time, in 2-year-old mice, 10-year-old dogs and 70-year-old people. Finding ways to damage one or two systems in a 6-week or 6-month-old mouse is not too hard to do, but the implications of such studies for improved understanding of aging per se are at best indirect and at worst imaginary and distracting.

  8. Acceleration of the aging process by oxygen

    NASA Technical Reports Server (NTRS)

    Miquel, J.; Lunderen, P. R.; Bensch, K. G.

    1975-01-01

    Tissue changes induced by hyperoxia have been compared with those of normal aging. Results of investigations using male flies prompt conclusion that normal aging, radiation syndrome, and hyperoxic injury share at least one common feature--lipid peroxidation damage to all mambranes resulting in accumulation of age pigment.

  9. Evolution of the microstructure of unmodified and polymer modified asphalt binders with aging in an accelerated weathering tester.

    PubMed

    Menapace, Ilaria; Masad, Eyad

    2016-09-01

    This paper presents findings on the evolution of the surface microstructure of two asphalt binders, one unmodified and one polymer modified, directly exposed to aging agents with increasing durations. The aging is performed using an accelerated weathering tester, where ultraviolet radiation, oxygen and an increased temperature are applied to the asphalt binder surface. Ultraviolet and dark cycles, which simulated the succession of day and night, alternated during the aging process, and also the temperature varied, which corresponded to typical summer day and night temperatures registered in the state of Qatar. Direct aging of an exposed binder surface is more effective in showing microstructural modifications than previously applied protocols, which involved the heat treatment of binders previously aged with standardized methods. With the new protocol, any molecular rearrangements in the binder surface after aging induced by the heat treatment is prevented. Optical photos show the rippling and degradation of the binder surface due to aging. Microstructure images obtained by means of atomic force microscopy show gradual alteration of the surface due to aging. The original relatively flat microstructure was substituted with a profoundly different microstructure, which significantly protrudes from the surface, and is characterized by various shapes, such as rods, round structures and finally 'flower' or 'leaf' structures. © 2016 The Authors Journal of Microscopy © 2016 Royal Microscopical Society.

  10. Diagnostic Challenges in Retinitis Pigmentosa: Genotypic Multiplicity and Phenotypic Variability

    PubMed Central

    Chang, Susie; Vaccarella, Leah; Olatunji, Sunday; Cebulla, Colleen; Christoforidis, John

    2011-01-01

    Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal disorders. Diagnosis can be challenging as more than 40 genes are known to cause non-syndromic RP and phenotypic expression can differ significantly resulting in variations in disease severity, age of onset, rate of progression, and clinical findings. We describe the clinical manifestations of RP, the more commonly known causative gene mutations, and the genotypic-phenotypic correlation of RP. PMID:22131872

  11. Effects of Bushen-Yizhi formula on age-related inflammation and oxidative stress in senescence-accelerated mice

    PubMed Central

    Hou, Xue-Qin; Song, Hou-Pan; Chen, Yun-Bo; Cheng, Shu-Yi; Fang, Shu-Huan; Zhang, Ji-Guo; Wang, Qi

    2018-01-01

    The present study aimed to investigate the possible effects and underlying molecular mechanism of Bushen-Yizhi formula (BSYZ), a traditional Chinese medicine, on age-related degeneration of brain physiology in senescence-accelerated mouse prone 8 (SAMP8) mice. SAMP8 mice (age, 6 months) were administered BSYZ (1.46, 2.92 and 5.84 g/kg/day) for 30 days. Morris water maze and step-down tests demonstrated that BSYZ significantly improved memory impairments in SAMP8 mice. In addition, BSYZ significantly enhanced the expression levels of peroxisome proliferator-activated receptor-γ and B-cell lymphoma extra-large, and downregulated the expression levels of inflammatory mediators, glial fibrillary acidic protein, cyclooxygenase-2, nuclear factor-κB and interleukin-1β in the brain compared with untreated SAMP8 mice. Furthermore, BSYZ reversed disordered superoxide dismutase activity, malondialdehyde content and glutathione peroxidase activity, and ameliorated apoptosis and histological alterations. The present study indicated that BSYZ may attenuate cognitive impairment in SAMP8 mice, and modulate inflammation, oxidative stress and neuronal apoptosis. These results suggested that BSYZ may have the potential to be further developed into a therapeutic agent for protection against age-related neurodegenerative diseases. PMID:29568888

  12. High phenotypic variability in Gerstmann-Sträussler-Scheinker disease.

    PubMed

    Smid, Jerusa; Studart, Adalberto; Landemberger, Michele Christine; Machado, Cleiton Fagundes; Nóbrega, Paulo Ribeiro; Canedo, Nathalie Henriques Silva; Schultz, Rodrigo Rizek; Naslavsky, Michel Satya; Rosemberg, Sérgio; Kok, Fernando; Chimelli, Leila; Martins, Vilma Regina; Nitrini, Ricardo

    2017-06-01

    Gerstmann-Sträussler-Scheinker is a genetic prion disease and the most common mutation is p.Pro102Leu. We report clinical, molecular and neuropathological data of seven individuals, belonging to two unrelated Brazilian kindreds, carrying the p.Pro102Leu. Marked differences among patients were observed regarding age at onset, disease duration and clinical presentation. In the first kindred, two patients had rapidly progressive dementia and three exhibited predominantly ataxic phenotypes with variable ages of onset and disease duration. In this family, age at disease onset in the mother and daughter differed by 39 years. In the second kindred, different phenotypes were also reported and earlier ages of onset were associated with 129 heterozygosis. No differences were associated with apoE genotype. In these kindreds, the codon 129 polymorphism could not explain the clinical variability and 129 heterozygosis was associated with earlier disease onset. Neuropathological examination in two patients confirmed the presence of typical plaques and PrPsc immunopositivity.

  13. Volatile organic compounds as non-invasive markers for plant phenotyping.

    PubMed

    Niederbacher, B; Winkler, J B; Schnitzler, J P

    2015-09-01

    Plants emit a great variety of volatile organic compounds (VOCs) that can actively participate in plant growth and protection against biotic and abiotic stresses. VOC emissions are strongly dependent on environmental conditions; the greatest ambiguity is whether or not the predicted change in climate will influence and modify plant-pest interactions that are mediated by VOCs. The constitutive and induced emission patterns between plant genotypes, species, and taxa are highly variable and can be used as pheno(chemo)typic markers to distinguish between different origins and provenances. In recent years significant progress has been made in molecular and genetic plant breeding. However, there is actually a lack of knowledge in functionally linking genotypes and phenotypes, particularly in analyses of plant-environment interactions. Plant phenotyping, the assessment of complex plant traits such as growth, development, tolerance, resistance, etc., has become a major bottleneck, and quantitative information on genotype-environment relationships is the key to addressing major future challenges. With increasing demand to support and accelerate progress in breeding for novel traits, the plant research community faces the need to measure accurately increasingly large numbers of plants and plant traits. In this review article, we focus on the promising outlook of VOC phenotyping as a fast and non-invasive measure of phenotypic dynamics. The basic principle is to define plant phenotypes according to their disease resistance and stress tolerance, which in turn will help in improving the performance and yield of economically relevant plants. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  14. A novel healthy blood pressure phenotype in the Long Life Family Study

    PubMed Central

    Marron, Megan M.; Singh, Jatinder; Boudreau, Robert M.; Christensen, Kaare; Cosentino, Stephanie; Feitosa, Mary F.; Minster, Ryan L.; Perls, Thomas; Schupf, Nicole; Sebastiani, Paola; Ukraintseva, Svetlana; Wojczynski, Mary K.; Newman, Anne B.

    2018-01-01

    Background Hypertension tends to run in families and has both genetic and environmental determinants. We assessed the hypothesis that a novel healthy blood pressure (BP) phenotype is also familial and sought to identify its associated factors. Methods We developed a healthy BP phenotype in the Long Life Family Study, a cohort of two-generation families selected for longevity. Participants from the offspring generation (n = 2211, ages 32–88) were classified as having healthy BP if their age-adjusted and sex-adjusted SBP z-score was between −1.5 and −0.5. Offspring on antihypertensive medications were classified as not having healthy BP. Families with at least two offspring (n = 419 families) were defined as meeting the healthy BP phenotype if at least two and at least 50% of their offspring had healthy BP. Results Among 2211 offspring, 476 (21.5%) met the healthy BP phenotype. When examining the 419 families, only 44 (10.5%) families met the criteria for the healthy BP phenotype. Both offspring and probands from families with healthy BP performed better on neuropsychological tests that place demands on complex attention and executive function when compared with offspring and probands from remaining families. Among families with the healthy BP phenotype compared with families without, a higher proportion of offspring met the American Heart Association definition of ideal cardiovascular health (10.8 versus 3.8%, respectively; driven by BP, smoking status, and BMI components). Conclusion In this cohort of familial longevity, few families had a novel healthy BP phenotype in multiple members. Families with this healthy BP phenotype may represent a specific pathway to familial longevity. PMID:28837423

  15. A novel healthy blood pressure phenotype in the Long Life Family Study.

    PubMed

    Marron, Megan M; Singh, Jatinder; Boudreau, Robert M; Christensen, Kaare; Cosentino, Stephanie; Feitosa, Mary F; Minster, Ryan L; Perls, Thomas; Schupf, Nicole; Sebastiani, Paola; Ukraintseva, Svetlana; Wojczynski, Mary K; Newman, Anne B

    2018-01-01

    Hypertension tends to run in families and has both genetic and environmental determinants. We assessed the hypothesis that a novel healthy blood pressure (BP) phenotype is also familial and sought to identify its associated factors. We developed a healthy BP phenotype in the Long Life Family Study, a cohort of two-generation families selected for longevity. Participants from the offspring generation (n = 2211, ages 32-88) were classified as having healthy BP if their age-adjusted and sex-adjusted SBP z-score was between -1.5 and -0.5. Offspring on antihypertensive medications were classified as not having healthy BP. Families with at least two offspring (n = 419 families) were defined as meeting the healthy BP phenotype if at least two and at least 50% of their offspring had healthy BP. Among 2211 offspring, 476 (21.5%) met the healthy BP phenotype. When examining the 419 families, only 44 (10.5%) families met the criteria for the healthy BP phenotype. Both offspring and probands from families with healthy BP performed better on neuropsychological tests that place demands on complex attention and executive function when compared with offspring and probands from remaining families. Among families with the healthy BP phenotype compared with families without, a higher proportion of offspring met the American Heart Association definition of ideal cardiovascular health (10.8 versus 3.8%, respectively; driven by BP, smoking status, and BMI components). In this cohort of familial longevity, few families had a novel healthy BP phenotype in multiple members. Families with this healthy BP phenotype may represent a specific pathway to familial longevity.

  16. Are objective measures of physical capability related to accelerated epigenetic age? Findings from a British birth cohort

    PubMed Central

    Cooper, Rachel; Howe, Laura D; Relton, Caroline L; Davey Smith, George; Teschendorff, Andrew; Widschwendter, Martin; Wong, Andrew; Kuh, Diana; Hardy, Rebecca

    2017-01-01

    Objectives Our aim was to investigate the association of epigenetic age and physical capability in later life. Having a higher epigenetic than chronological age (known as age acceleration (AA)) has been found to be associated with an increased rate of mortality. Similarly, physical capability has been proposed as a marker of ageing due to its consistent associations with mortality. Setting The MRC National Survey of Health and Development (NSHD) cohort study. Participants We used data from 790 women from the NSHD who had DNA methylation data available. Design Epigenetic age was calculated using buccal cell (n=790) and matched blood tissue (n=152) from 790 female NSHD participants. We investigated the association of AA at age 53 with changes in physical capability in women from ages 53 to 60–64. Regression models of change in each measure of physical capability on AA were conducted. Secondary analysis focused on the relationship between AA and smoking, alcohol, body mass index (BMI) and socioeconomic position. Outcome measures Three objective measures of physical capability were used: grip strength, standing balance time and chair rise speed. Results Epigenetic age was lower than chronological age (mean 53.4) for both blood (50.3) and buccal cells (42.8). AA from blood was associated with a greater decrease in grip strength from ages 53 to 60–64 (0.42 kg decrease per year of AA, 95% CI 0.03, 0.82 kg; p=0.03, n=152), but no associations were observed with standing balance time or chair rise speed. Current smoking and lower BMI were associated with lower epigenetic age from buccal cells. Conclusions We found evidence that AA in blood is associated with a greater decrease in grip strength in British females aged between 53 and 60–64, but no association with standing balance time or chair rise speed was found. PMID:29092899

  17. Drosophila Clock Is Required in Brain Pacemaker Neurons to Prevent Premature Locomotor Aging Independently of Its Circadian Function

    PubMed Central

    Issa, Abdul-Raouf; Seugnet, Laurent; Klarsfeld, André

    2017-01-01

    Circadian clocks control many self-sustained rhythms in physiology and behavior with approximately 24-hour periodicity. In many organisms, oxidative stress and aging negatively impact the circadian system and sleep. Conversely, loss of the clock decreases resistance to oxidative stress, and may reduce lifespan and speed up brain aging and neurodegeneration. Here we examined the effects of clock disruptions on locomotor aging and longevity in Drosophila. We found that lifespan was similarly reduced in three arrhythmic mutants (ClkAR, cyc0 and tim0) and in wild-type flies under constant light, which stops the clock. In contrast, ClkAR mutants showed significantly faster age-related locomotor deficits (as monitored by startle-induced climbing) than cyc0 and tim0, or than control flies under constant light. Reactive oxygen species accumulated more with age in ClkAR mutant brains, but this did not appear to contribute to the accelerated locomotor decline of the mutant. Clk, but not Cyc, inactivation by RNA interference in the pigment-dispersing factor (PDF)-expressing central pacemaker neurons led to similar loss of climbing performance as ClkAR. Conversely, restoring Clk function in these cells was sufficient to rescue the ClkAR locomotor phenotype, independently of behavioral rhythmicity. Accelerated locomotor decline of the ClkAR mutant required expression of the PDF receptor and correlated to an apparent loss of dopaminergic neurons in the posterior protocerebral lateral 1 (PPL1) clusters. This neuronal loss was rescued when the ClkAR mutation was placed in an apoptosis-deficient background. Impairing dopamine synthesis in a single pair of PPL1 neurons that innervate the mushroom bodies accelerated locomotor decline in otherwise wild-type flies. Our results therefore reveal a novel circadian-independent requirement for Clk in brain circadian neurons to maintain a subset of dopaminergic cells and avoid premature locomotor aging in Drosophila. PMID:28072817

  18. Minimal impact of age and housing temperature on the metabolic phenotype of Acc2-/- mice.

    PubMed

    Brandon, Amanda E; Stuart, Ella; Leslie, Simon J; Hoehn, Kyle L; James, David E; Kraegen, Edward W; Turner, Nigel; Cooney, Gregory J

    2016-03-01

    An important regulator of fatty acid oxidation (FAO) is the allosteric inhibition of CPT-1 by malonyl-CoA produced by the enzyme acetyl-CoA carboxylase 2 (ACC2). Initial studies suggested that deletion of Acc2 (Acacb) increased fat oxidation and reduced adipose tissue mass but in an independently generated strain of Acc2 knockout mice we observed increased whole-body and skeletal muscle FAO and a compensatory increase in muscle glycogen stores without changes in glucose tolerance, energy expenditure or fat mass in young mice (12-16 weeks). The aim of the present study was to determine whether there was any effect of age or housing at thermoneutrality (29 °C; which reduces total energy expenditure) on the phenotype of Acc2 knockout mice. At 42-54 weeks of age, male WT and Acc2(-/-) mice had similar body weight, fat mass, muscle triglyceride content and glucose tolerance. Consistent with younger Acc2(-/-) mice, aged Acc2(-/-) mice showed increased whole-body FAO (24 h average respiratory exchange ratio=0.95±0.02 and 0.92±0.02 for WT and Acc2(-/-) mice respectively, P<0.05) and skeletal muscle glycogen content (+60%, P<0.05) without any detectable change in whole-body energy expenditure. Hyperinsulinaemic-euglycaemic clamp studies revealed no difference in insulin action between groups with similar glucose infusion rates and tissue glucose uptake. Housing Acc2(-/-) mice at 29 °C did not alter body composition, glucose tolerance or the effects of fat feeding compared with WT mice. These results confirm that manipulation of Acc2 may alter FAO in mice, but this has little impact on body composition or insulin action. © 2016 Society for Endocrinology.

  19. XPD Helicase Structures And Activities: Insights Into the Cancer And Aging Phenotypes From XPD Mutations

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Fan, L.; Fuss, J.O.; Cheng, Q.J.

    2009-05-18

    Mutations in XPD helicase, required for nucleotide excision repair (NER) as part of the transcription/repair complex TFIIH, cause three distinct phenotypes: cancer-prone xeroderma pigmentosum (XP), or aging disorders Cockayne syndrome (CS), and trichothiodystrophy (TTD). To clarify molecular differences underlying these diseases, we determined crystal structures of the XPD catalytic core from Sulfolobus acidocaldarius and measured mutant enzyme activities. Substrate-binding grooves separate adjacent Rad51/RecA-like helicase domains (HD1, HD2) and an arch formed by 4FeS and Arch domains. XP mutations map along the HD1 ATP-binding edge and HD2 DNA-binding channel and impair helicase activity essential for NER. XP/CS mutations both impair helicasemore » activity and likely affect HD2 functional movement. TTD mutants lose or retain helicase activity but map to sites in all four domains expected to cause framework defects impacting TFIIH integrity. These results provide a foundation for understanding disease consequences of mutations in XPD and related 4Fe-4S helicases including FancJ.« less

  20. XPD Helicase Structures and Activities: Insights into the Cancer and Aging Phenotypes from XPD Mutations

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tainer, John; Fan, Li; Fuss, Jill O.

    2008-06-02

    Mutations in XPD helicase, required for nucleotide excision repair (NER) as part of the transcription/repair complex TFIIH, cause three distinct phenotypes: cancer-prone xeroderma pigmentosum (XP), or aging disorders Cockayne syndrome (CS), and trichothiodystrophy (TTD). To clarify molecular differences underlying these diseases, we determined crystal structures of the XPD catalytic core from Sulfolobus acidocaldarius and measured mutant enzyme activities. Substrate-binding grooves separate adjacent Rad51/RecA-like helicase domains (HD1, HD2) and an arch formed by 4FeS and Arch domains. XP mutations map along the HD1 ATP-binding edge and HD2 DNA-binding channel and impair helicase activity essential for NER. XP/CS mutations both impair helicasemore » activity and likely affect HD2 functional movement. TTD mutants lose or retain helicase activity but map to sites in all four domains expected to cause framework defects impacting TFIIH integrity. These results provide a foundation for understanding disease consequences of mutations in XPD and related 4Fe-4S helicases including FancJ.« less

  1. A custom multi-modal sensor suite and data analysis pipeline for aerial field phenotyping

    NASA Astrophysics Data System (ADS)

    Bartlett, Paul W.; Coblenz, Lauren; Sherwin, Gary; Stambler, Adam; van der Meer, Andries

    2017-05-01

    Our group has developed a custom, multi-modal sensor suite and data analysis pipeline to phenotype crops in the field using unpiloted aircraft systems (UAS). This approach to high-throughput field phenotyping is part of a research initiative intending to markedly accelerate the breeding process for refined energy sorghum varieties. To date, single rotor and multirotor helicopters, roughly 14 kg in total weight, are being employed to provide sensor coverage over multiple hectaresized fields in tens of minutes. The quick, autonomous operations allow for complete field coverage at consistent plant and lighting conditions, with low operating costs. The sensor suite collects data simultaneously from six sensors and registers it for fusion and analysis. High resolution color imagery targets color and geometric phenotypes, along with lidar measurements. Long-wave infrared imagery targets temperature phenomena and plant stress. Hyperspectral visible and near-infrared imagery targets phenotypes such as biomass and chlorophyll content, as well as novel, predictive spectral signatures. Onboard spectrometers and careful laboratory and in-field calibration techniques aim to increase the physical validity of the sensor data throughout and across growing seasons. Off-line processing of data creates basic products such as image maps and digital elevation models. Derived data products include phenotype charts, statistics, and trends. The outcome of this work is a set of commercially available phenotyping technologies, including sensor suites, a fully integrated phenotyping UAS, and data analysis software. Effort is also underway to transition these technologies to farm management users by way of streamlined, lower cost sensor packages and intuitive software interfaces.

  2. Early phenotypical diagnoses in Trembler-J mice model.

    PubMed

    Rosso, Gonzalo; Cal, Karina; Canclini, Lucía; Damián, Juan Pablo; Ruiz, Paul; Rodríguez, Héctor; Sotelo, José Roberto; Vazquez, Cristina; Kun, Alejandra

    2010-06-30

    Pmp-22 mutant mice (Trembler-J: B6.D2-Pmp22/J), are used as a model to study Charcot-Marie-Tooth type 1A (CMT1A). The identification of individual genotypes is a routine in the management of the Tr(J) colony. The earliest phenotypic manifestation of the pmp-22 mutation is just about 20th postnatal days, when pups begin to tremble. In this study, a rapid and simple diagnostic method was developed by modifying the Tail Suspension Test (MTST) to determine the difference between the Tr(J) and the wild-type mice phenotype. The animal behavioral phenotypes generated during the test were consistent with the specific genotype of each animal. The MTST allowed us to infer the heterozygous genotype in early postnatal stages, at 11 days after birth. The motor impairment of Tr(J) mice was also analyzed by a Fixed Bar Test (FBT), which revealed the disease evolution according to age. The main advantages of MTST are its objectivity, simplicity, and from the viewpoint of animal welfare, it is a non-invasive technique that combined with his rapidity show its very well applicability for use from an early age in these mice. Copyright 2010 Elsevier B.V. All rights reserved.

  3. Systems-level analysis of age-related macular degeneration reveals global biomarkers and phenotype-specific functional networks

    PubMed Central

    2012-01-01

    Background Age-related macular degeneration (AMD) is a leading cause of blindness that affects the central region of the retinal pigmented epithelium (RPE), choroid, and neural retina. Initially characterized by an accumulation of sub-RPE deposits, AMD leads to progressive retinal degeneration, and in advanced cases, irreversible vision loss. Although genetic analysis, animal models, and cell culture systems have yielded important insights into AMD, the molecular pathways underlying AMD's onset and progression remain poorly delineated. We sought to better understand the molecular underpinnings of this devastating disease by performing the first comparative transcriptome analysis of AMD and normal human donor eyes. Methods RPE-choroid and retina tissue samples were obtained from a common cohort of 31 normal, 26 AMD, and 11 potential pre-AMD human donor eyes. Transcriptome profiles were generated for macular and extramacular regions, and statistical and bioinformatic methods were employed to identify disease-associated gene signatures and functionally enriched protein association networks. Selected genes of high significance were validated using an independent donor cohort. Results We identified over 50 annotated genes enriched in cell-mediated immune responses that are globally over-expressed in RPE-choroid AMD phenotypes. Using a machine learning model and a second donor cohort, we show that the top 20 global genes are predictive of AMD clinical diagnosis. We also discovered functionally enriched gene sets in the RPE-choroid that delineate the advanced AMD phenotypes, neovascular AMD and geographic atrophy. Moreover, we identified a graded increase of transcript levels in the retina related to wound response, complement cascade, and neurogenesis that strongly correlates with decreased levels of phototransduction transcripts and increased AMD severity. Based on our findings, we assembled protein-protein interactomes that highlight functional networks likely to be

  4. Age-specific influence of wheezing phenotypes on pre-adolescent and adolescent health-related quality of life.

    PubMed

    Braig, Stefanie; Brandt, Stephanie; Wabitsch, Martin; Florath, Ines; Brenner, Hermann; Rothenbacher, Dietrich; Genuneit, Jon

    2014-12-01

    Asthma is associated with diminished health-related quality of life (HRQoL). Particularly in adolescence, asthma may be under-diagnosed and undertreated or poorly managed. Therefore, we aimed to determine the association between childhood wheezing phenotypes rather than asthma and adolescent HRQoL in children aged 10-17 yr. We analyzed the data from two prospective population-based cohort studies (n = 604 and n = 1804) conducted in southern Germany with baseline assessments in 2000 and 2006 and follow-ups at frequent intervals. Parent-reported wheeze was categorized into never, early transient, persistent, and late-onset wheeze. We assessed child-reported HRQoL in seven scales using the validated KINDL-R. Multivariate linear regression models were computed. Participants with late-onset wheeze had significantly lower values in all HRQoL scales, but physical well-being compared to never wheezers. Early transient wheeze was negatively associated with three HRQoL scales only (family, school, and total). These effects were confined to the oldest age group (≥13.5 yr) in one study. Persistent wheeze was not associated with HRQoL. In teenagers, late-onset wheezers seem to be particularly vulnerable for impairments in psychosocial aspects of health-related quality of life. They may therefore require particular attention with regard to education about asthma management and potentially family-based psychosocial intervention. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Preterm nutritional intake and MRI phenotype at term age: a prospective observational study

    PubMed Central

    Vasu, Vimal; Durighel, Giuliana; Thomas, Louise; Malamateniou, Christina; Bell, Jimmy D; Rutherford, Mary A; Modi, Neena

    2014-01-01

    Objective To describe (1) the relationship between nutrition and the preterm-at-term infant phenotype, (2) phenotypic differences between preterm-at-term infants and healthy term born infants and (3) relationships between somatic and brain MRI outcomes. Design Prospective observational study. Setting UK tertiary neonatal unit. Participants Preterm infants (<32 weeks gestation) (n=22) and healthy term infants (n=39) Main outcome measures Preterm nutrient intake; total and regional adipose tissue (AT) depot volumes; brain volume and proximal cerebral arterial vessel tortuosity (CAVT) in preterm infants and in term infants. Results Preterm nutrition was deficient in protein and high in carbohydrate and fat. Preterm nutrition was not related to AT volumes, brain volume or proximal CAVT score; a positive association was noted between human milk intake and proximal CAVT score (r=0.44, p=0.05). In comparison to term infants, preterm infants had increased total adiposity, comparable brain volumes and reduced proximal CAVT scores. There was a significant negative correlation between deep subcutaneous abdominal AT volume and brain volume in preterm infants (r=−0.58, p=0.01). Conclusions Though there are significant phenotypic differences between preterm infants at term and term infants, preterm macronutrient intake does not appear to be a determinant. Our preliminary data suggest that (1) human milk may exert a beneficial effect on cerebral arterial vessel tortuosity and (2) there is a negative correlation between adiposity and brain volume in preterm infants at term. Further work is warranted to see if our findings can be replicated and to understand the causal mechanisms. PMID:24860004

  6. Optimum Selection Age for Wood Density in Loblolly Pine

    Treesearch

    D.P. Gwaze; K.J. Harding; R.C. Purnell; Floyd E. Brigwater

    2002-01-01

    Genetic and phenotypic parameters for core wood density of Pinus taeda L. were estimated for ages ranging from 5 to 25 years at two sites in southern United States. Heritability estimates on an individual-tree basis for core density were lower than expected (0.20-0.31). Age-age genetic correlations were higher than phenotypic correlations,...

  7. Comparative study of ageing, heat treatment and accelerated carbonation for stabilization of municipal solid waste incineration bottom ash in view of reducing regulated heavy metal/metalloid leaching.

    PubMed

    Santos, Rafael M; Mertens, Gilles; Salman, Muhammad; Cizer, Özlem; Van Gerven, Tom

    2013-10-15

    This study compared the performance of four different approaches for stabilization of regulated heavy metal and metalloid leaching from municipal solid waste incineration bottom ash (MSWI-BA): (i) short term (three months) heap ageing, (ii) heat treatment, (iii) accelerated moist carbonation, and (iv) accelerated pressurized slurry carbonation. Two distinct types of MSWI-BA were tested in this study: one originating from a moving-grate furnace incineration operation treating exclusively household refuse (sample B), and another originating from a fluid-bed furnace incineration operation that treats a mixture of household and light industrial wastes (sample F). The most abundant elements in the ashes were Si (20-27 wt.%) and Ca (16-19 wt.%), followed by significant quantities of Fe, Al, Na, S, K, Mg, Ti, and Cl. The main crystalline substances present in the fresh ashes were Quartz, Calcite, Apatite, Anhydrite and Gehlenite, while the amorphous fraction ranged from 56 to 73 wt.%. The leaching values of all samples were compared to the Flemish (NEN 7343) and the Walloon (DIN 38414) regulations from Belgium. Batch leaching of the fresh ashes at natural pH showed that seven elements exceeded at least one regulatory limit (Ba, Cr, Cu, Mo, Pb, Se and Zn), and that both ashes had excess basicity (pH > 12). Accelerated carbonation achieved significant reduction in ash basicity (9.3-9.9); lower than ageing (10.5-12.2) and heat treatment (11.1-12.1). For sample B, there was little distinction between the leaching results of ageing and accelerated carbonation with respect to regulatory limits; however carbonation achieved comparatively lower leaching levels. Heat treatment was especially detrimental to the leaching of Cr. For sample F, ageing was ineffective and heat treatment had marginally better results, while accelerated carbonation delivered the most effective performance, with slurry carbonation meeting all DIN limits. Slurry carbonation was deemed the most

  8. Heavy Ion Acceleration at J-PARC

    NASA Astrophysics Data System (ADS)

    SATO, Susumu

    2018-02-01

    J-PARC, the Japan Proton Accelerator Research Complex, is an accelerator, which provides a high-intensity proton beam. Recently as a very attractive project, the acceleration of heavy ions produced by supplementary ion sources, called J-PARC-HI, is seriously contemplated by domestic as well as international communities. The planned facility would accelerate heavy ions up to U92+ with a beam energy 20 AGeV ( of 6.2 AGeV). The highlight of the J-PARC-HI project is its very high beam rate up to 1011 Hz, which will enable the study of very rare events. Taking advantage of this high intensity, J-PARC-HI will carry out frontier studies of new and rare observables in this energy region: (i) nuclear medium modification of chiral property of vector mesons through low-mass di-lepton signal, (ii) QCD critical pointcharacterization through event-by-event fluctuation signals of particle production, (iii) systematic measurements related to the equation of state through collective flow signal or two-particle momentum correlation signal, or (iv) the search of hyper nuclei with multi strangeness including or exceeding S = 3. The current plan of J-PARC-HI aims to carrying out the first experimental measurements in 2025.

  9. PhenoLines: Phenotype Comparison Visualizations for Disease Subtyping via Topic Models.

    PubMed

    Glueck, Michael; Naeini, Mahdi Pakdaman; Doshi-Velez, Finale; Chevalier, Fanny; Khan, Azam; Wigdor, Daniel; Brudno, Michael

    2018-01-01

    PhenoLines is a visual analysis tool for the interpretation of disease subtypes, derived from the application of topic models to clinical data. Topic models enable one to mine cross-sectional patient comorbidity data (e.g., electronic health records) and construct disease subtypes-each with its own temporally evolving prevalence and co-occurrence of phenotypes-without requiring aligned longitudinal phenotype data for all patients. However, the dimensionality of topic models makes interpretation challenging, and de facto analyses provide little intuition regarding phenotype relevance or phenotype interrelationships. PhenoLines enables one to compare phenotype prevalence within and across disease subtype topics, thus supporting subtype characterization, a task that involves identifying a proposed subtype's dominant phenotypes, ages of effect, and clinical validity. We contribute a data transformation workflow that employs the Human Phenotype Ontology to hierarchically organize phenotypes and aggregate the evolving probabilities produced by topic models. We introduce a novel measure of phenotype relevance that can be used to simplify the resulting topology. The design of PhenoLines was motivated by formative interviews with machine learning and clinical experts. We describe the collaborative design process, distill high-level tasks, and report on initial evaluations with machine learning experts and a medical domain expert. These results suggest that PhenoLines demonstrates promising approaches to support the characterization and optimization of topic models.

  10. Aging-related renal injury and inflammation are associated with downregulation of Klotho and induction of RIG-I/NF-κB signaling pathway in senescence-accelerated mice.

    PubMed

    Zeng, Yi; Wang, Ping-Han; Zhang, Mao; Du, Jun-Rong

    2016-02-01

    The predominant distribution of the antiaging Klotho protein in both the kidneys and brain may point to its essential role in protecting against dysfunction of the kidney-brain axis during the aging process. Our previous study showed that the downregulation of Klotho was involved in aging-related cognitive impairment in aged senescence-accelerated mouse prone-8 (SAMP8) mice. The present study investigated the potential role of Klotho in aging-associated inflammation and renal injury. Age- and gender-matched groups of SAMP8 mice and their corresponding normal control senescence-accelerated mouse resistant-1 (SAMR1) were used to investigate the potential role of Klotho in aging-associated inflammation and renal injury. Compared with aged SAMR1 controls, early-stage chronic kidney disease (CKD), which is associated with an increase in the urinary albumin-to-creatinine ratio, inflammatory cell infiltration, glomerulosclerosis, and tubulointerstitial fibrosis, was observed in aged SAMP8 mice. Furthermore, the aging-related loss of Klotho-induced activation of the retinoic acid-inducible gene 1/nuclear factor-κB (RIG-I/NF-κB) signaling pathway and subsequent production of the proinflammatory mediators tumor necrosis factor α, interleukin-6, and inducible nitric oxide synthase in the kidneys of aged SAMP8 mice compared with SAMR1 controls. The present results suggest that aging-related inflammation and the development of early-stage CKD are likely associated with the downregulation of Klotho and induction of the RIG-I/NF-κB signaling pathway in 12-month-old SAMP8 mice. Moreover, aged SAMP8 mice with cognitive deficits and renal damage may be a potential mouse model for investigating the kidney-brain axis in the aging process.

  11. Effects of accelerated artificial daylight aging on bending strength and bonding of glass fibers in fiber-embedded maxillofacial silicone prostheses.

    PubMed

    Hatamleh, Muhanad M; Watts, David C

    2010-07-01

    The purpose of this study was to test the effect of different periods of accelerated artificial daylight aging on bond strength of glass fiber bundles embedded into maxillofacial silicone elastomer and on bending strength of the glass fiber bundles. Forty specimens were fabricated by embedding resin-impregnated fiber bundles (1.5-mm diameter, 20-mm long) into maxillofacial silicone elastomer. Specimens were randomly allocated into four groups, and each group was subjected to different periods of accelerated daylight aging as follows (in hours); 0, 200, 400, and 600. The aging cycle included continuous exposure to quartz-filtered visible daylight (irradiance 760 W/m(2)) under an alternating weathering cycle (wet for 18 minutes, dry for 102 minutes). Pull-out tests were performed to evaluate bond strength between fiber bundles and silicone using a universal testing machine at 1 mm/min crosshead speed. Also a three-point bending test was performed to evaluate bending strength of the fiber bundles. One-way ANOVA and Bonferroni post hoc tests were carried out to detect statistical significance (p < 0.05). Mean (SD) values of maximum pull-out forces (in N) for groups 1 to 4 were: 13.63 (7.45), 19.67 (1.37), 13.58 (2.61), and 10.37 (2.52). Group 2 exhibited the highest pull-out force that was statistically significant when compared to the other groups. Maximum bending strengths of fiber bundles were in the range of 917.72 MPa to 1124.06 MPa. Bending strength significantly increased after 200 and 400 hours of aging only. After 200 hours of exposure to artificial daylight and moisture conditions, bond strength between glass fibers and heat-cured silicones is optimal, and the bending strength of the glass fiber bundles is enhanced.

  12. Radioisotope Dating with Accelerators.

    ERIC Educational Resources Information Center

    Muller, Richard A.

    1979-01-01

    Explains a new method of detecting radioactive isotopes by counting their accelerated ions rather than the atoms that decay during the counting period. This method increases the sensitivity by several orders of magnitude, and allows one to find the ages of much older and smaller samples. (GA)

  13. Genotype-phenotype associations in WT1 glomerulopathy.

    PubMed

    Lipska, Beata S; Ranchin, Bruno; Iatropoulos, Paraskevas; Gellermann, Jutta; Melk, Anette; Ozaltin, Fatih; Caridi, Gianluca; Seeman, Tomas; Tory, Kalman; Jankauskiene, Augustina; Zurowska, Aleksandra; Szczepanska, Maria; Wasilewska, Anna; Harambat, Jerome; Trautmann, Agnes; Peco-Antic, Amira; Borzecka, Halina; Moczulska, Anna; Saeed, Bassam; Bogdanovic, Radovan; Kalyoncu, Mukaddes; Simkova, Eva; Erdogan, Ozlem; Vrljicak, Kristina; Teixeira, Ana; Azocar, Marta; Schaefer, Franz

    2014-05-01

    WT1 mutations cause a wide spectrum of renal and extrarenal manifestations. Here we evaluated disease prevalence, phenotype spectrum, and genotype-phenotype correlations of 61 patients with WT1-related steroid-resistant nephrotic syndrome relative to 700 WT1-negative patients, all with steroid-resistant nephrotic syndrome. WT1 patients more frequently presented with chronic kidney disease and hypertension at diagnosis and exhibited more rapid disease progression. Focal segmental glomerulosclerosis was equally prevalent in both cohorts, but diffuse mesangial sclerosis was largely specific for WT1 disease and was present in 34% of cases. Sex reversal and/or urogenital abnormalities (52%), Wilms tumor (38%), and gonadoblastoma (5%) were almost exclusive to WT1 disease. Missense substitutions affecting DNA-binding residues were associated with diffuse mesangial sclerosis (74%), early steroid-resistant nephrotic syndrome onset, and rapid progression to ESRD. Truncating mutations conferred the highest Wilms tumor risk (78%) but typically late-onset steroid-resistant nephrotic syndrome. Intronic (KTS) mutations were most likely to present as isolated steroid-resistant nephrotic syndrome (37%) with a median onset at an age of 4.5 years, focal segmental glomerulosclerosis on biopsy, and slow progression (median ESRD age 13.6 years). Thus, there is a wide range of expressivity, solid genotype-phenotype associations, and a high risk and significance of extrarenal complications in WT1-associated nephropathy. We suggest that all children with steroid-resistant nephrotic syndrome undergo WT1 gene screening.

  14. Phenotypic Effects of Salt and Heat Stress over Three Generations in Arabidopsis thaliana

    PubMed Central

    Suter, Léonie; Widmer, Alex

    2013-01-01

    Current and predicted environmental change will force many organisms to adapt to novel conditions, especially sessile organisms such as plants. It is therefore important to better understand how plants react to environmental stress and to what extent genotypes differ in such responses. It has been proposed that adaptation to novel conditions could be facilitated by heritable epigenetic changes induced by environmental stress, independent of genetic variation. Here we assessed phenotypic effects of heat and salt stress within and across three generations using four highly inbred Arabidopsis thaliana genotypes (Col, Cvi, Ler and Sha). Salt stress generally decreased fitness, but genotypes were differently affected, suggesting that susceptibility of A. thaliana to salt stress varies among genotypes. Heat stress at an early rosette stage had less detrimental effects but accelerated flowering in three out of four accessions. Additionally, we found three different modes of transgenerational effects on phenotypes, all harboring the potential of being adaptive: heat stress in previous generations induced faster rosette growth in Sha, both under heat and control conditions, resembling a tracking response, while in Cvi, the phenotypic variance of several traits increased, resembling diversified bet-hedging. Salt stress experienced in earlier generations altered plant architecture of Sha under salt but not control conditions, similar to transgenerational phenotypic plasticity. However, transgenerational phenotypic effects depended on the type of stress as well as on genotype, suggesting that such effects may not be a general response leading to adaptation to novel environmental conditions in A. thaliana. PMID:24244719

  15. TOMATOMA Update: Phenotypic and Metabolite Information in the Micro-Tom Mutant Resource.

    PubMed

    Shikata, Masahito; Hoshikawa, Ken; Ariizumi, Tohru; Fukuda, Naoya; Yamazaki, Yukiko; Ezura, Hiroshi

    2016-01-01

    TOMATOMA (http://tomatoma.nbrp.jp/) is a tomato mutant database providing visible phenotypic data of tomato mutant lines generated by ethylmethane sulfonate (EMS) treatment or γ-ray irradiation in the genetic background of Micro-Tom, a small and rapidly growing variety. To increase mutation efficiency further, mutagenized M3 seeds were subjected to a second round of EMS treatment; M3M1 populations were generated. These plants were self-pollinated, and 4,952 lines of M3M2 mutagenized seeds were generated. We checked for visible phenotypes in the M3M2 plants, and 618 mutant lines with 1,194 phenotypic categories were identified. In addition to the phenotypic information, we investigated Brix values and carotenoid contents in the fruits of individual mutants. Of 466 samples from 171 mutant lines, Brix values and carotenoid contents were between 3.2% and 11.6% and 6.9 and 37.3 µg g(-1) FW, respectively. This metabolite information concerning the mutant fruits would be useful in breeding programs as well as for the elucidation of metabolic regulation. Researchers are able to browse and search this phenotypic and metabolite information and order seeds of individual mutants via TOMATOMA. Our new Micro-Tom double-mutagenized populations and the metabolic information could provide a valuable genetic toolkit to accelerate tomato research and potential breeding programs. © The Author 2015. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  16. Planning for an Accelerated School. A Two Day Workshop (Stanford, California, November 17-18, 1988). Illinois Network of Accelerated Schools.

    ERIC Educational Resources Information Center

    Illinois State Board of Education, Springfield. Dept. of School Improvement Services.

    The thesis of this conference report is that acceleration is a much more effective method than remediation for bringing at-risk children into the educational mainstream at an early age. The papers summarized in the report provide a background on the history, politics, and demography of at-risk students and suggest applications of acceleration to…

  17. An mtDNA mutation accelerates liver aging by interfering with the ROS response and mitochondrial life cycle.

    PubMed

    Niemann, Jan; Johne, Cindy; Schröder, Susanne; Koch, Franziska; Ibrahim, Saleh M; Schultz, Julia; Tiedge, Markus; Baltrusch, Simone

    2017-01-01

    Mitochondrial dysfunction affects liver metabolism, but it remains unclear whether this interferes with normal liver aging. We investigated several mitochondrial pathways in hepatocytes and liver tissue from a conplastic mouse strain compared with the control C57BL/6NTac strain over 18 months of life. The C57BL/6NTac-mtNODLtJ mice differed from C57BL/6NTac mice by a point mutation in mitochondrial-encoded subunit 3 of cytochrome c oxidase. Young C57BL/6NTac-mtNODLtJ mice showed reduced mitochondrial metabolism but similar reactive oxygen species (ROS) production to C57BL/6NTac mice. Whereas ROS increased almost equally up to 9 months in both strains, different mitochondrial adaptation strategies resulted in decreasing ROS in advanced age in C57BL/6NTac mice, but persistent ROS production in C57BL/6NTac-mtNODLtJ mice. Only the conplastic strain developed elongated mitochondrial networks with artificial loop structures, depressed autophagy, high mitochondrial respiration and up-regulated antioxidative response. Our results indicate that mtDNA mutations accelerate liver ballooning degeneration and carry a serious risk of premature organ aging. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Cardiac Phenotype of Prehypertrophic Fabry Disease.

    PubMed

    Nordin, Sabrina; Kozor, Rebecca; Baig, Shanat; Abdel-Gadir, Amna; Medina-Menacho, Katia; Rosmini, Stefania; Captur, Gabriella; Tchan, Michel; Geberhiwot, Tarekegn; Murphy, Elaine; Lachmann, Robin; Ramaswami, Uma; Edwards, Nicola C; Hughes, Derralynn; Steeds, Richard P; Moon, James C

    2018-06-01

    Fabry disease (FD) is a rare and treatable X-linked lysosomal storage disorder. Cardiac involvement determines outcomes; therefore, detecting early changes is important. Native T1 by cardiovascular magnetic resonance is low, reflecting sphingolipid storage. Early phenotype development is familiar in hypertrophic cardiomyopathy but unexplored in FD. We explored the prehypertrophic cardiac phenotype of FD and the role of storage. A prospective, international multicenter observational study of 100 left ventricular hypertrophy-negative FD patients (mean age: 39±15 years; 19% male) and 35 age- and sex-matched healthy volunteers (mean age: 40±14 years; 25% male) who underwent cardiovascular magnetic resonance, including native T1 and late gadolinium enhancement, and 12-lead ECG. In FD, 41% had a low native T1 using a single septal region of interest, but this increased to 59% using a second slice because early native T1 lowering was patchy. ECG abnormalities were present in 41% and twice as common with low native T1 (53% versus 24%; P =0.005). When native T1 was low, left ventricular maximum wall thickness, indexed mass, and ejection fraction were higher (maximum wall thickness 9±1.5 versus 8±1.4 mm, P <0.005; indexed left ventricular mass 63±10 versus 58±9 g/m 2 , P <0.05; and left ventricular ejection fraction 73±8% versus 69±7%, P <0.01). Late gadolinium enhancement was more likely when native T1 was low (27% versus 6%; P =0.01). FD had higher maximal apical fractal dimensions compared with healthy volunteers (1.27±0.06 versus 1.24±0.04; P <0.005) and longer anterior mitral valve leaflets (23±2 mm versus 21±3 mm; P <0.005). There is a detectable prehypertrophic phenotype in FD consisting of storage (low native T1), structural, functional, and ECG changes. © 2018 The Authors.

  19. [Genotype/phenotype correlation in autism: genetic models and phenotypic characterization].

    PubMed

    Bonnet-Brilhault, F

    2011-02-01

    Autism spectrum disorders are a class of conditions categorized by communication problems, ritualistic behaviors, and deficits in social behaviors. This class of disorders merges a heterogeneous group of neurodevelopmental disorders regarding some phenotypic and probably physiopathological aspects. Genetic basis is well admitted, however, considering phenotypic and genotypic heterogeneity, correspondences between genotype and phenotype have yet to be established. To better identify such correspondences, genetic models have to be identified and phenotypic markers have to be characterized. Recent insights show that a variety of genetic mechanisms may be involved in autism spectrum disorders, i.e. single gene disorders, copy number variations and polygenic mechanisms. These current genetic models are described. Regarding clinical aspects, several approaches can be used in genetic studies. Nosographical approach, especially with the concept of autism spectrum disorders, merges a large group of disorders with clinical heterogeneity and may fail to identify clear genotype/phenotype correlations. Dimensional approach referred in genetic studies to the notion of "Broad Autism Phenotype" related to a constellation of language, personality, and social-behavioral features present in relatives that mirror the symptom domains of autism, but are much milder in expression. Studies of this broad autism phenotype may provide a potentially important complementary approach for detecting the genes involved in these domains. However, control population used in those studies need to be well characterized too. Identification of endophenotypes seems to offer more promising results. Endophenotypes, which are supposed to be more proximal markers of gene action in the same biological pathway, linking genes and complex clinical symptoms, are thought to be less genetically complex than the broader disease phenotype, indexing a limited aspect of genetic risk for the disorder as a whole. However

  20. A novel diagnostic tool reveals mitochondrial pathology in human diseases and aging.

    PubMed

    Scheibye-Knudsen, Morten; Scheibye-Alsing, Karsten; Canugovi, Chandrika; Croteau, Deborah L; Bohr, Vilhelm A

    2013-03-01

    The inherent complex and pleiotropic phenotype of mitochondrial diseases poses a significant diagnostic challenge for clinicians as well as an analytical barrier for scientists. To overcome these obstacles we compiled a novel database, www.mitodb.com, containing the clinical features of primary mitochondrial diseases. Based on this we developed a number of qualitative and quantitative measures, enabling us to determine whether a disorder can be characterized as mitochondrial. These included a clustering algorithm, a disease network, a mitochondrial barcode and two scoring algorithms. Using these tools we detected mitochondrial involvement in a number of diseases not previously recorded as mitochondrial. As a proof of principle Cockayne syndrome, ataxia with oculomotor apraxia 1 (AOA1), spinocerebellar ataxia with axonal neuropathy 1 (SCAN1) and ataxia-telangiectasia have recently been shown to have mitochondrial dysfunction and those diseases showed strong association with mitochondrial disorders. We next evaluated mitochondrial involvement in aging and detected two distinct categories of accelerated aging disorders, one of them being associated with mitochondrial dysfunction. Normal aging seemed to associate stronger with the mitochondrial diseases than the non-mitochondrial partially supporting a mitochondrial theory of aging.

  1. GEneSTATION 1.0: a synthetic resource of diverse evolutionary and functional genomic data for studying the evolution of pregnancy-associated tissues and phenotypes

    PubMed Central

    Kim, Mara; Cooper, Brian A.; Venkat, Rohit; Phillips, Julie B.; Eidem, Haley R.; Hirbo, Jibril; Nutakki, Sashank; Williams, Scott M.; Muglia, Louis J.; Capra, J. Anthony; Petren, Kenneth; Abbot, Patrick; Rokas, Antonis; McGary, Kriston L.

    2016-01-01

    Mammalian gestation and pregnancy are fast evolving processes that involve the interaction of the fetal, maternal and paternal genomes. Version 1.0 of the GEneSTATION database (http://genestation.org) integrates diverse types of omics data across mammals to advance understanding of the genetic basis of gestation and pregnancy-associated phenotypes and to accelerate the translation of discoveries from model organisms to humans. GEneSTATION is built using tools from the Generic Model Organism Database project, including the biology-aware database CHADO, new tools for rapid data integration, and algorithms that streamline synthesis and user access. GEneSTATION contains curated life history information on pregnancy and reproduction from 23 high-quality mammalian genomes. For every human gene, GEneSTATION contains diverse evolutionary (e.g. gene age, population genetic and molecular evolutionary statistics), organismal (e.g. tissue-specific gene and protein expression, differential gene expression, disease phenotype), and molecular data types (e.g. Gene Ontology Annotation, protein interactions), as well as links to many general (e.g. Entrez, PubMed) and pregnancy disease-specific (e.g. PTBgene, dbPTB) databases. By facilitating the synthesis of diverse functional and evolutionary data in pregnancy-associated tissues and phenotypes and enabling their quick, intuitive, accurate and customized meta-analysis, GEneSTATION provides a novel platform for comprehensive investigation of the function and evolution of mammalian pregnancy. PMID:26567549

  2. Early constraints in sexual dimorphism: survival benefits of feminized phenotypes.

    PubMed

    López-Rull, I; Vergara, P; Martínez-Padilla, J; Fargallo, J A

    2016-02-01

    Sexual dimorphism (SD) has evolved in response to selection pressures that differ between sexes. Since such pressures change across an individual's life, SD may vary within age classes. Yet, little is known about how selection on early phenotypes may drive the final SD observed in adults. In many dimorphic species, juveniles resemble adult females rather than adult males, meaning that out of the selective pressures established by sexual selection feminized phenotypes may be adaptive. If true, fitness benefits of early female-like phenotypes may constrain the expression of male phenotypes in adulthood. Using the common kestrel Falco tinnunculus as a study model, we evaluated the fitness advantages of expressing more feminized phenotypes at youth. Although more similar to adult females than to adult males, common kestrel fledglings are still sexually dimorphic in size and coloration. Integrating morphological and chromatic variables, we analysed the phenotypic divergence between sexes as a measure of how much each individual looks like the sex to which it belongs (phenotypic sexual resemblance, PSR). We then tested the fitness benefits associated with PSR by means of the probability of recruitment in the population. We found a significant interaction between PSR and sex, showing that in both sexes more feminized phenotypes recruited more into the population than less feminized phenotypes. Moreover, males showed lower PSR than females and a higher proportion of incorrect sex classifications. These findings suggest that the mechanisms in males devoted to resembling female phenotypes in youth, due to a trend to increase fitness through more feminized phenotypes, may provide a mechanism to constrain the SD in adulthood. © 2015 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2015 European Society For Evolutionary Biology.

  3. Accelerated aging characteristics of three yttria-stabilized tetragonal zirconia polycrystalline dental materials.

    PubMed

    Flinn, Brian D; deGroot, Dirk A; Mancl, Lloyd A; Raigrodski, Ariel J

    2012-10-01

    Concerns have been expressed about the effect of aging on the mechanical properties of zirconia. The purpose of this study was to assess the accelerated aging characteristics of 3 commercially available yttria-stabilized tetragonal zirconia polycrystalline (Y-TZP) materials by exposing specimens to hydrothermal treatments at 134°C, 0.2 MPa and 180°C, 1.0 MPa in steam. Thin bars of Y-TZP from 3 manufacturers, Lava, Zirkonzahn, and Zirprime, n=30 for each brand (22 × 3 × 0.2 mm), were cut and ground from blocks and sintered according to the manufacturer's specifications. Control specimens (n=10) for each brand were evaluated in the as-received condition. Experimental specimens were artificially aged at standard autoclave sterilization conditions,134°C at 0.2 MPa (n=5 per group at 50, 100, 150, and 200 hours) and standard industrial ceramic aging conditions, 180°C at 1.0 MPa (n=5 per group at 8, 16, 24, 28, and 48 hours). Tetragonal to monoclinic transformation was measured by using X-ray diffraction (XRD) for all groups. Flexural strength was measured in 4-point bending (ASTM1161-B) for all groups. Fracture surfaces were examined by scanning electron microscopy (SEM). Data were analyzed as a function of aging time. The statistical comparisons were based on the log value and 2-way ANOVA with heteroscedasticity-consistent standard errors used to compare mean strength among conditions (α=.05). After 200 hours at 134°C and 0.2 MPa, flexural strength (SD) decreased significantly from 1156 (87.6) MPa to 829.5 (71) MPa for Lava; 1406 (243) MPa to 882.7 (91) MPa for Zirkonzahn; and 1126 (92.4) MPa to 976 (36.4) MPa for Zirprime with P<.001 for all 3 comparisons. After 200 hours at 134°C and 0.2 MPa, some tetragonal crystals transformed to the monoclinic phase. The relative XRD peak intensity of the monoclinic to tetragonal crystal phases increased from 0.07 to 1.82 for Lava, from 0.06 to 2.43 for Zirkonzahn, and from 0.05 to 0.53 for Zirprime. After 28 hours at 180

  4. Reduced Gut Acidity Induces an Obese-Like Phenotype in Drosophila melanogaster and in Mice

    PubMed Central

    Yen, Jui-Hung; Kuo, Ping-Chang; Yeh, Sheng-Rong; Lin, Hung-Yu; Fu, Tsai-Feng; Wu, Ming-Shiang; Wang, Horng-Dar; Wang, Pei-Yu

    2015-01-01

    In order to identify genes involved in stress and metabolic regulation, we carried out a Drosophila P-element-mediated mutagenesis screen for starvation resistance. We isolated a mutant, m2, that showed a 23% increase in survival time under starvation conditions. The P-element insertion was mapped to the region upstream of the vha16-1 gene, which encodes the c subunit of the vacuolar-type H+-ATPase. We found that vha16-1 is highly expressed in the fly midgut, and that m2 mutant flies are hypomorphic for vha16-1 and also exhibit reduced midgut acidity. This deficit is likely to induce altered metabolism and contribute to accelerated aging, since vha16-1 mutant flies are short-lived and display increases in body weight and lipid accumulation. Similar phenotypes were also induced by pharmacological treatment, through feeding normal flies and mice with a carbonic anhydrase inhibitor (acetazolamide) or proton pump inhibitor (PPI, lansoprazole) to suppress gut acid production. Our study may thus provide a useful model for investigating chronic acid suppression in patients. PMID:26436771

  5. The correlation between serum AMH and HOMA-IR among PCOS phenotypes.

    PubMed

    Wiweko, Budi; Indra, Indra; Susanto, Cynthia; Natadisastra, Muharam; Hestiantoro, Andon

    2018-02-09

    Polycystic ovarian syndrome (PCOS) is known to be one of the most prevalent endocrine disorders affecting reproductive age women. One of the endocrine disorder is hyperinsulinemia, which corresponds with the severity of PCOS. However, the pathogenesis of PCOS is not fully understood, but one theory of anti-mullerian hormone (AMH) has been proposed as one of the factor related to the degree of severity of PCOS. However, there are no clear correlation between levels of AMH with the incidence of insulin resistance in PCOS patients especially in Indonesia. This is a cross-sectional study involving reproductive age women aged 18-35 years. Subjects were recruited consecutively at Dr. Cipto Mangunkusumo General Hospital between 2011 until 2014. PCOS women diagnosed using 2003 Rotterdam criteria were categorized into four different PCOS phenotypes. Subsequently, serum level of AMH and HOMA-IR was measured and evaluated with correlation tests performed using SPSS 11.0 RESULTS: A total of 125 PCOS patients were included in a study conducted within a 3-year period. Phenotype 1 (anovulation, hyperandrogenism, and polycystic ovaries) shows the highest levels of AMH and HOMA-IR, which decreases in accordance to severity level (p < 0.005). The positive correlation between AMH and HOMA-IR persisted even after adjusting for BMI in multivariate analysis. There was a positive correlation between serum AMH and HOMA IR levels. Serum AMH and HOMA IR levels were significantly different across the four PCOS phenotypes; with the highest values were present with phenotype 1.

  6. Phenotypes of asthma revisited upon the presence of atopy.

    PubMed

    Nieves, Ana; Magnan, Antoine; Boniface, Stéphanie; Proudhon, Hervé; Lanteaume, André; Romanet, Stéphanie; Vervloet, Daniel; Godard, Philippe

    2005-03-01

    Immunological studies claimed that atopic and non-atopic asthma share more similarities than differences. However, these two phenotypes of asthma are considered to be distinguishable upon distinct clinical patterns, which were not systematically assessed before in a large population. We studied characteristics discriminating atopic from non-atopic asthma among 751 asthmatic patients and 80 factors were analysed in univariate and multivariate analysis. Age, age of onset of asthma, female/male ratio were higher in non-atopic (n=200) than in atopic (n=551) asthmatics. Familial asthma, seasonal symptoms, rhinitis, conjunctivitis, allergen-triggered symptoms, improvement in altitude, exercise-induced asthma were associated with atopy. Non-atopic asthmatics displayed lower FEV(1) and FVC. Smoking was more frequent and asthma was more severe in these patients. Younger age, early onset, male sex, rhinitis and smoking were independent factors discriminating atopic from non-atopic asthma. This study establishes in a large population of asthmatics that although similarities exist between atopic and non-atopic asthma, two clinical phenotypes can still distinguish both kinds of asthma.

  7. Assessing sex assignment concordance with genotype and phenotype.

    PubMed

    Suresh, Deepa; Crawford, Jessica; Axelrad, Marni E; Gunn, Sheila K; McCullough, Laurence; Smith, O' Brian; Sutton, Vernon R; Roth, David; Karaviti, Lefkothea P; Dietrich, Jennifer E

    2013-03-14

    To catalogue patients with DSD and to assess the concordance of genotype and phenotype with sex assignment at birth compared to sex assignment before and following assessment by a Gender Medicine Team (GMT) at one institution, as an initial step in formulating standardized guidelines for management of these conditions. After obtaining IRB approval, a retrospective chart review was conducted patients seen in the Gender Medicine Clinic (GMC) between 2006-2009 at Texas Children's Hospital (TCH), Houston, Texas. McNemar's test and Kappa agreement provided associations of various factors with sex assignment at birth prior to GMT assessment and after GMT assessment. Forty-seven patients seen in the GMC with confirmed DSD. Forty-seven patients met the inclusion criteria. The mean age of the patients at the time of GMT evaluation was 9.1+/-6.1 years; 61.7% had male karyotype, and 38.3% had female karyotype; 51.1% had a male external phenotype, 42.6% had a female external phenotype, and 6.4% had phenotypic ambiguity. Sex assignment was concordant with genotype and phenotype in 63.8% and 86.4%, respectively of cases at the time of birth and in 76.6% and 97.7%, respectively, of cases after assessment by GMT. Long-term outcomes are needed to establish standardized practice guidelines for decision-making.

  8. Cerebral palsy: phenotypes and risk factors in term singletons born small for gestational age.

    PubMed

    Freire, Gabrielle; Shevell, Michael; Oskoui, Maryam

    2015-03-01

    Children born small for gestational age (SGA) are at increased risk of developing cerebral palsy (CP). The pathophysiology behind this association remains unclear. We compare the clinical profile of children with CP born SGA to other children with CP. We hypothesize that differences noted will support antenatal causes of CP in children born SGA. We conducted a retrospective cohort study of term singletons with CP, extracting data from the Canadian Cerebral Palsy Registry. SGA was determined as birth weight for gestational age and sex below the tenth percentile. Mothers of children with CP born SGA were more likely to be of African-American ethnicity (RR 2.54, 95% CI 1.20-5.39), have intrauterine infections (RR 2.22, 95% CI 1.09-4.50) and have gestational hypertension (RR 1.78, 95% CI 1.06-3.00). Children with CP born SGA had smaller head circumferences at birth (p < 0.001) and higher frequencies of emergency cesarean-section (RR 1.53, 95% CI 1.22-1.92), birth asphyxia (RR 1.53, 95% CI 1.0-2.32), and placental abnormalities (RR 1.45, 95% CI 1.00-2.10). Children with CP born SGA had greater fine motor (RR 1.46, 95% CI 1.02-2.11), gross motor (RR 1.53, 95% CI 1.12-2.10) and communication impairment (RR 1.24, 95% CI 1.10-1.40), and a higher frequency of cognitive impairment (RR 1.33, 95% CI 1.06-1.69). Children with CP born SGA have different clinical factors and phenotypic profiles than other children with CP. These differences support the hypothesis of antenatal and perinatal causes of CP in children born SGA. Future case control studies would be desired to further define this causal pathway. Copyright © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  9. Acceleration modules in linear induction accelerators

    NASA Astrophysics Data System (ADS)

    Wang, Shao-Heng; Deng, Jian-Jun

    2014-05-01

    The Linear Induction Accelerator (LIA) is a unique type of accelerator that is capable of accelerating kilo-Ampere charged particle current to tens of MeV energy. The present development of LIA in MHz bursting mode and the successful application into a synchrotron have broadened LIA's usage scope. Although the transformer model is widely used to explain the acceleration mechanism of LIAs, it is not appropriate to consider the induction electric field as the field which accelerates charged particles for many modern LIAs. We have examined the transition of the magnetic cores' functions during the LIA acceleration modules' evolution, distinguished transformer type and transmission line type LIA acceleration modules, and re-considered several related issues based on transmission line type LIA acceleration module. This clarified understanding should help in the further development and design of LIA acceleration modules.

  10. Obesity-induced chronic inflammation in high fat diet challenged C57BL/6J mice is associated with acceleration of age-dependent renal amyloidosis

    PubMed Central

    van der Heijden, Roel A.; Bijzet, Johan; Meijers, Wouter C.; Yakala, Gopala K.; Kleemann, Robert; Nguyen, Tri Q.; de Boer, Rudolf A.; Schalkwijk, Casper G.; Hazenberg, Bouke P. C.; Tietge, Uwe J. F.; Heeringa, Peter

    2015-01-01

    Obesity-induced inflammation presumably accelerates the development of chronic kidney diseases. However, little is known about the sequence of these inflammatory events and their contribution to renal pathology. We investigated the effects of obesity on the evolution of age-dependent renal complications in mice in conjunction with the development of renal and systemic low-grade inflammation (LGI). C57BL/6J mice susceptible to develop age-dependent sclerotic pathologies with amyloid features in the kidney, were fed low (10% lard) or high-fat diets (45% lard) for 24, 40 and 52 weeks. HFD-feeding induced overt adiposity, altered lipid and insulin homeostasis, increased systemic LGI and adipokine release. HFD-feeding also caused renal upregulation of pro-inflammatory genes, infiltrating macrophages, collagen I protein, increased urinary albumin and NGAL levels. HFD-feeding severely aggravated age-dependent structural changes in the kidney. Remarkably, enhanced amyloid deposition rather than sclerosis was observed. The degree of amyloidosis correlated significantly with body weight. Amyloid deposits stained positive for serum amyloid A (SAA) whose plasma levels were chronically elevated in HFD mice. Our data indicate obesity-induced chronic inflammation as a risk factor for the acceleration of age-dependent renal amyloidosis and functional impairment in mice, and suggest that obesity-enhanced chronic secretion of SAA may be the driving factor behind this process. PMID:26563579

  11. Obesity-induced chronic inflammation in high fat diet challenged C57BL/6J mice is associated with acceleration of age-dependent renal amyloidosis.

    PubMed

    van der Heijden, Roel A; Bijzet, Johan; Meijers, Wouter C; Yakala, Gopala K; Kleemann, Robert; Nguyen, Tri Q; de Boer, Rudolf A; Schalkwijk, Casper G; Hazenberg, Bouke P C; Tietge, Uwe J F; Heeringa, Peter

    2015-11-13

    Obesity-induced inflammation presumably accelerates the development of chronic kidney diseases. However, little is known about the sequence of these inflammatory events and their contribution to renal pathology. We investigated the effects of obesity on the evolution of age-dependent renal complications in mice in conjunction with the development of renal and systemic low-grade inflammation (LGI). C57BL/6J mice susceptible to develop age-dependent sclerotic pathologies with amyloid features in the kidney, were fed low (10% lard) or high-fat diets (45% lard) for 24, 40 and 52 weeks. HFD-feeding induced overt adiposity, altered lipid and insulin homeostasis, increased systemic LGI and adipokine release. HFD-feeding also caused renal upregulation of pro-inflammatory genes, infiltrating macrophages, collagen I protein, increased urinary albumin and NGAL levels. HFD-feeding severely aggravated age-dependent structural changes in the kidney. Remarkably, enhanced amyloid deposition rather than sclerosis was observed. The degree of amyloidosis correlated significantly with body weight. Amyloid deposits stained positive for serum amyloid A (SAA) whose plasma levels were chronically elevated in HFD mice. Our data indicate obesity-induced chronic inflammation as a risk factor for the acceleration of age-dependent renal amyloidosis and functional impairment in mice, and suggest that obesity-enhanced chronic secretion of SAA may be the driving factor behind this process.

  12. Dynamic Environmental Photosynthetic Imaging Reveals Emergent Phenotypes

    DOE PAGES

    Cruz, Jeffrey A.; Savage, Linda J.; Zegarac, Robert; ...

    2016-06-22

    Understanding and improving the productivity and robustness of plant photosynthesis requires high-throughput phenotyping under environmental conditions that are relevant to the field. Here we demonstrate the dynamic environmental photosynthesis imager (DEPI), an experimental platform for integrated, continuous, and high-throughput measurements of photosynthetic parameters during plant growth under reproducible yet dynamic environmental conditions. Using parallel imagers obviates the need to move plants or sensors, reducing artifacts and allowing simultaneous measurement on large numbers of plants. As a result, DEPI can reveal phenotypes that are not evident under standard laboratory conditions but emerge under progressively more dynamic illumination. We show examples inmore » mutants of Arabidopsis of such “emergent phenotypes” that are highly transient and heterogeneous, appearing in different leaves under different conditions and depending in complex ways on both environmental conditions and plant developmental age. Finally, these emergent phenotypes appear to be caused by a range of phenomena, suggesting that such previously unseen processes are critical for plant responses to dynamic environments.« less

  13. Dynamic phenotypic restructuring of the CD4 and CD8 T-cell subsets with age in healthy humans: a compartmental model analysis.

    PubMed

    Jackola, D R; Hallgren, H M

    1998-11-16

    In healthy humans, phenotypic restructuring occurs with age within the CD3+ T-lymphocyte complement. This is characterized by a non-linear decrease of the percentage of 'naive' (CD45RA+) cells and a corresponding non-linear increase of the percentage of 'memory' (CD45R0+) cells among both the CD4+ and CD8+ T-cell subsets. We devised a simple compartmental model to study the age-dependent kinetics of phenotypic restructuring. We also derived differential equations whose parameters determined yearly gains minus losses of the percentage and absolute numbers of circulating naive cells, yearly gains minus losses of the percentage and absolute numbers of circulating memory cells, and the yearly rate of conversion of naive to memory cells. Solutions of these evaluative differential equations demonstrate the following: (1) the memory cell complement 'resides' within its compartment for a longer time than the naive cell complement within its compartment for both CD4 and CD8 cells; (2) the average, annual 'turnover rate' is the same for CD4 and CD8 naive cells. In contrast, the average, annual 'turnover rate' for memory CD8 cells is 1.5 times that of memory CD4 cells; (3) the average, annual conversion rate of CD4 naive cells to memory cells is twice that of the CD8 conversion rate; (4) a transition in dynamic restructuring occurs during the third decade of life that is due to these differences in turnover and conversion rates, between and from naive to memory cells.

  14. Accelerated ageing of blended OPC cements

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Quillin, K.C.; Duerden, S.L.; Majumdar, A.J.

    1994-12-31

    An accelerated experimental technique using high water:cement ratios has been developed to study the long term hydration of blended cements that may be used in a repository for the disposal of radioactive waste. This technique has been used to investigate the hydration reactions of Ordinary Portland Cement (OPC) blended with ground granulated blastfurnace slag (ggbs) or pulverised fuel ash (pfa). The effects of high sulphate-bearing and high carbonate-bearing ground waters on the compounds formed on hydration were investigated. Solid/solution compositional data were collected during the course of the hydration process for periods up to 2 years. Thomsonite, thaumasite, afwillite andmore » a tobermorite-like phase were found in addition to the expected cement hydration products. The pH of the aqueous solution in contact with 60 pfa:40 OPC blends hydrated at 90{degrees}C fell to below 8. This is lower than the value required to inhibit the corrosion of steel canisters in a repository. The pH of the aqueous solution in contact with OPC and 75 ggbs:25 OPC blends remained above 11, although if the ground waters in contact with the OPC/ggbs blends were periodically replaced the pH eventually fell below 10.« less

  15. Coral reef fishes exhibit beneficial phenotypes inside marine protected areas

    PubMed Central

    Carroll, Jessica; Rynerson, Kristen W.; Matthews, Danielle F.; Turingan, Ralph G.

    2018-01-01

    Human fishing effort is size-selective, preferentially removing the largest individuals from harvested stocks. Intensive, size-specific fishing mortality induces directional shifts in phenotypic frequencies towards the predominance of smaller and earlier-maturing individuals, which are among the primary causes of declining fish biomass. Fish that reproduce at smaller size and younger age produce fewer, smaller, and less viable larvae, severely reducing the reproductive capacity of harvested populations. Marine protected areas (MPAs) are extensively utilized in coral reefs for fisheries management, and are thought to mitigate the impacts of size-selective fishing mortality and supplement fished stocks through larval export. However, empirical evidence of disparities in fitness-relevant phenotypes between MPAs and adjacent fished reefs is necessary to validate this assertion. Here, we compare key life-history traits in three coral-reef fishes (Acanthurus nigrofuscus, Ctenochaetus striatus, and Parupeneus multifasciatus) between MPAs and fished reefs in the Philippines. Results of our analyses support previous hypotheses regarding the impacts of MPAs on phenotypic traits. Asymptotic length (Linf) and growth rates (K) differed between conspecifics in MPAs and fished reefs, with protected populations exhibiting phenotypes that are known to confer higher fecundity. Additionally, populations demonstrated increases in length at 50% maturity (L50) inside MPAs compared to adjacent areas, although age at 50% maturity (A50) did not appear to be impacted by MPA establishment. Shifts toward advantageous phenotypes were most common in the oldest and largest MPAs, but occurred in all of the MPAs examined. These results suggest that MPAs may provide protection against the impacts of size-selective harvest on life-history traits in coral-reef fishes. PMID:29470525

  16. Tif1γ regulates the TGF-β1 receptor and promotes physiological aging of hematopoietic stem cells.

    PubMed

    Quéré, Ronan; Saint-Paul, Laetitia; Carmignac, Virginie; Martin, Romain Z; Chrétien, Marie-Lorraine; Largeot, Anne; Hammann, Arlette; Pais de Barros, Jean-Paul; Bastie, Jean-Noël; Delva, Laurent

    2014-07-22

    The hematopoietic system declines with age. Myeloid-biased differentiation and increased incidence of myeloid malignancies feature aging of hematopoietic stem cells (HSCs), but the mechanisms involved remain uncertain. Here, we report that 4-mo-old mice deleted for transcription intermediary factor 1γ (Tif1γ) in HSCs developed an accelerated aging phenotype. To reinforce this result, we also show that Tif1γ is down-regulated in HSCs during aging in 20-mo-old wild-type mice. We established that Tif1γ controls TGF-β1 receptor (Tgfbr1) turnover. Compared with young HSCs, Tif1γ(-/-) and old HSCs are more sensitive to TGF-β signaling. Importantly, we identified two populations of HSCs specifically discriminated by Tgfbr1 expression level and provided evidence of the capture of myeloid-biased (Tgfbr1(hi)) and myeloid-lymphoid-balanced (Tgfbr1(lo)) HSCs. In conclusion, our data provide a new paradigm for Tif1γ in regulating the balance between lymphoid- and myeloid-derived HSCs through TGF-β signaling, leading to HSC aging.

  17. Genetic and Environmental Influences on Obesity-Related Phenotypes in Chinese Twins Reared Apart and Together.

    PubMed

    Zhou, Bin; Gao, Wenjing; Lv, Jun; Yu, Canqing; Wang, Shengfeng; Liao, Chunxiao; Pang, Zengchang; Cong, Liming; Dong, Zhong; Wu, Fan; Wang, Hua; Wu, Xianping; Jiang, Guohong; Wang, Xiaojie; Wang, Binyou; Cao, Weihua; Li, Liming

    2015-07-01

    The relative importance of genetic and environmental influences on obesity-related phenotypes remains unclear, and few studies have targeted the Chinese population. Here, we used Chinese twins reared apart and together to explore genetic and environmental influences on body mass index (BMI), waist circumference (WC) and waist-height ratio (WHtR), further to differentiate phenotype heritability between different age groups and genders separately and to differentiate influences of rearing environment and correlated environment. Phenotype heritability was calculated using the structural equation model in 11,401 twin pairs aged 25-85 years. BMI (0.70, 95 % confidence interval (CI) 0.66-0.74) of the total population was highly heritable, while WC (0.53, 95 %CI 0.50-0.57) and WHtR (0.48, 95 %CI 0.45-0.51) were moderately heritable. Age and gender stratified analyses found higher heritability in the younger group and males than the older group and females. The correlated environment had a greater influence on the phenotypes than the rearing environment, especially on WC and WHtR, indicating that more correlated environment actions should be taken to prevent the rising trend of abdominal obesity.

  18. Serum Biochemical Phenotypes in the Domestic Dog

    PubMed Central

    Chang, Yu-Mei; Hadox, Erin; Szladovits, Balazs; Garden, Oliver A.

    2016-01-01

    The serum or plasma biochemical profile is essential in the diagnosis and monitoring of systemic disease in veterinary medicine, but current reference intervals typically take no account of breed-specific differences. Breed-specific hematological phenotypes have been documented in the domestic dog, but little has been published on serum biochemical phenotypes in this species. Serum biochemical profiles of dogs in which all measurements fell within the existing reference intervals were retrieved from a large veterinary database. Serum biochemical profiles from 3045 dogs were retrieved, of which 1495 had an accompanying normal glucose concentration. Sixty pure breeds plus a mixed breed control group were represented by at least 10 individuals. All analytes, except for sodium, chloride and glucose, showed variation with age. Total protein, globulin, potassium, chloride, creatinine, cholesterol, total bilirubin, ALT, CK, amylase, and lipase varied between sexes. Neutering status significantly impacted all analytes except albumin, sodium, calcium, urea, and glucose. Principal component analysis of serum biochemical data revealed 36 pure breeds with distinctive phenotypes. Furthermore, comparative analysis identified 23 breeds with significant differences from the mixed breed group in all biochemical analytes except urea and glucose. Eighteen breeds were identified by both principal component and comparative analysis. Tentative reference intervals were generated for breeds with a distinctive phenotype identified by comparative analysis and represented by at least 120 individuals. This is the first large-scale analysis of breed-specific serum biochemical phenotypes in the domestic dog and highlights potential genetic components of biochemical traits in this species. PMID:26919479

  19. Psychological Adjustment in a College-Level Program of Marked Academic Acceleration.

    ERIC Educational Resources Information Center

    Robinson, Nancy M.; Janos, Paul M.

    1986-01-01

    The questionnaire responses of 24 markedly accelerated young students at the University of Washington were compared with those of 24 regular-aged university students, 23 National Merit Scholors, and 27 students who had qualified for acceleration but instead elected to participate in high school. Accelerants appeared as well adjusted as all…

  20. Young adult survivors of childhood acute lymphoblastic leukemia show evidence of chronic inflammation and cellular aging.

    PubMed

    Ariffin, Hany; Azanan, Mohamad Shafiq; Abd Ghafar, Sayyidatul Syahirah; Oh, Lixian; Lau, Kee Hie; Thirunavakarasu, Tharshanadhevasheri; Sedan, Atiqah; Ibrahim, Kamariah; Chan, Adelyne; Chin, Tong Foh; Liew, Fong Fong; Jeyamogan, Shareni; Rosli, Erda Syerena; Baharudin, Rashidah; Yap, Tsiao Yi; Skinner, Roderick; Lum, Su Han; Hainaut, Pierre

    2017-11-01

    Large epidemiologic studies have reported the premature onset of age-related conditions, such as ischemic heart disease and diabetes mellitus, in childhood cancer survivors, decades earlier than in their peers. The authors investigated whether young adult survivors of childhood acute lymphoblastic leukemia (ALL) have a biologic phenotype of cellular ageing and chronic inflammation. Plasma inflammatory cytokines were measured using a cytometric bead array in 87 asymptomatic young adult survivors of childhood ALL (median age, 25 years; age range, 18-35 years) who attended annual follow-up clinic and compared with healthy, age-matched and sex-matched controls. Leukocyte telomere length (LTL) was measured using Southern blot analysis. Survivors had significant elevation of plasma interleukin-2 (IL-2), IL-10, IL-17a, and high-sensitivity C-reactive protein levels (all P < .05). A raised high-sensitivity C-reactive protein level (>0.8 mg/dL) was related to increased odds of having metabolic syndrome (odds ratio, 7.256; 95% confidence interval, 1.501-35.074). Survivors also had significantly shorter LTL compared with controls (median, 9866 vs 10,392 base pairs; P = .021). Compared with published data, LTL in survivors was similar to that in healthy individuals aged 20 years older. Survivors who received cranial irradiation had shorter LTL compared with those who had not (P = .013). Asymptomatic young adult survivors of childhood ALL demonstrate a biologic profile of chronic inflammation and telomere attrition, consistent with an early onset of cellular processes that drive accelerated aging. These processes may explain the premature development of age-related chronic conditions in childhood cancer survivors. Understanding their molecular basis may facilitate targeted interventions to disrupt the accelerated aging process and its long-term impact on overall health. Cancer 2017;123:4207-4214. © 2017 American Cancer Society. © 2017 American Cancer Society.

  1. Accelerated aging of preservative-treated structural plywood

    Treesearch

    C. Adam Senalik; Robert J. Ross; Samuel L. Zelinka; Stan T. Lebow; Zhiyong Cai

    2017-01-01

    In this study, the changes in physical properties and preservative retention of high-grade plywood when subjected to artificial aging processes were examined. The plywood was 15/32-in.-thick panels manufactured from southern yellow pine A and C grades of veneer. The artificial aging processes consisted of three primary mechanisms of degradation: thermal degradation,...

  2. PON1-192 phenotype and genotype assessments in 918 subjects of the Stanislas cohort study.

    PubMed

    Vincent-Viry, Monique; Sass, Catherine; Bastien, Sabine; Aguillon, Dominique; Siest, Gérard; Visvikis, Sophie

    2003-04-01

    This study describes the factors of variation of the enzymes related to the PON1-192 phenotype assessment, i.e., basal paraoxonase, salt-stimulated paraoxonase and arylesterase activities, and compares the PON1-192 phenotype to the PON1-192 genotype assessments in supposedly healthy subjects issued from the Stanislas cohort study. The studied population included 918 subjects, i.e., 221 families including 441 adults and 477 children aged 4 to 58 years. Potential determinants such as age, gender, body mass index, alcohol and tobacco consumption, and oral contraceptive intake have been studied. The PON ratio (salt-stimulated paraoxonase/arylesterase) was trimodally distributed and the cut-off values used to differentiate the two homozygous (AA and BB phenotypes) from the heterozygous (AB phenotype) subjects were 3.0 and 7.0 in this study. In males, basal paraoxonase and salt-stimulated paraoxonase activities were not affected by alcohol consumption and current smoking, but basal paraoxonase activity was decreased by 15% by current smoking and was increased by 15% by oral contraceptive intake in females as was the salt-stimulated paraoxonase activity. The level of discordance between phenotype and genotype assessments was 7.2% (66/918). Most of the discrepancies were observed between the BB and AB phenotypes (4.25%).

  3. The phenotypic manifestations of rare genic CNVs in autism spectrum disorder

    PubMed Central

    Merikangas, A K; Segurado, R; Heron, E A; Anney, R J L; Paterson, A D; Cook, E H; Pinto, D; Scherer, S W; Szatmari, P; Gill, M; Corvin, A P; Gallagher, L

    2015-01-01

    Significant evidence exists for the association between copy number variants (CNVs) and Autism Spectrum Disorder (ASD); however, most of this work has focused solely on the diagnosis of ASD. There is limited understanding of the impact of CNVs on the ‘sub-phenotypes' of ASD. The objective of this paper is to evaluate associations between CNVs in differentially brain expressed (DBE) genes or genes previously implicated in ASD/intellectual disability (ASD/ID) and specific sub-phenotypes of ASD. The sample consisted of 1590 cases of European ancestry from the Autism Genome Project (AGP) with a diagnosis of an ASD and at least one rare CNV impacting any gene and a core set of phenotypic measures, including symptom severity, language impairments, seizures, gait disturbances, intelligence quotient (IQ) and adaptive function, as well as paternal and maternal age. Classification analyses using a non-parametric recursive partitioning method (random forests) were employed to define sets of phenotypic characteristics that best classify the CNV-defined groups. There was substantial variation in the classification accuracy of the two sets of genes. The best variables for classification were verbal IQ for the ASD/ID genes, paternal age at birth for the DBE genes and adaptive function for de novo CNVs. CNVs in the ASD/ID list were primarily associated with communication and language domains, whereas CNVs in DBE genes were related to broader manifestations of adaptive function. To our knowledge, this is the first study to examine the associations between sub-phenotypes and CNVs genome-wide in ASD. This work highlights the importance of examining the diverse sub-phenotypic manifestations of CNVs in ASD, including the specific features, comorbid conditions and clinical correlates of ASD that comprise underlying characteristics of the disorder. PMID:25421404

  4. The phenotypic manifestations of rare genic CNVs in autism spectrum disorder.

    PubMed

    Merikangas, A K; Segurado, R; Heron, E A; Anney, R J L; Paterson, A D; Cook, E H; Pinto, D; Scherer, S W; Szatmari, P; Gill, M; Corvin, A P; Gallagher, L

    2015-11-01

    Significant evidence exists for the association between copy number variants (CNVs) and Autism Spectrum Disorder (ASD); however, most of this work has focused solely on the diagnosis of ASD. There is limited understanding of the impact of CNVs on the 'sub-phenotypes' of ASD. The objective of this paper is to evaluate associations between CNVs in differentially brain expressed (DBE) genes or genes previously implicated in ASD/intellectual disability (ASD/ID) and specific sub-phenotypes of ASD. The sample consisted of 1590 cases of European ancestry from the Autism Genome Project (AGP) with a diagnosis of an ASD and at least one rare CNV impacting any gene and a core set of phenotypic measures, including symptom severity, language impairments, seizures, gait disturbances, intelligence quotient (IQ) and adaptive function, as well as paternal and maternal age. Classification analyses using a non-parametric recursive partitioning method (random forests) were employed to define sets of phenotypic characteristics that best classify the CNV-defined groups. There was substantial variation in the classification accuracy of the two sets of genes. The best variables for classification were verbal IQ for the ASD/ID genes, paternal age at birth for the DBE genes and adaptive function for de novo CNVs. CNVs in the ASD/ID list were primarily associated with communication and language domains, whereas CNVs in DBE genes were related to broader manifestations of adaptive function. To our knowledge, this is the first study to examine the associations between sub-phenotypes and CNVs genome-wide in ASD. This work highlights the importance of examining the diverse sub-phenotypic manifestations of CNVs in ASD, including the specific features, comorbid conditions and clinical correlates of ASD that comprise underlying characteristics of the disorder.

  5. Early brain injury alters the blood-brain barrier phenotype in parallel with β-amyloid and cognitive changes in adulthood.

    PubMed

    Pop, Viorela; Sorensen, Dane W; Kamper, Joel E; Ajao, David O; Murphy, M Paul; Head, Elizabeth; Hartman, Richard E; Badaut, Jérôme

    2013-02-01

    Clinical studies suggest that traumatic brain injury (TBI) hastens cognitive decline and development of neuropathology resembling brain aging. Blood-brain barrier (BBB) disruption following TBI may contribute to the aging process by deregulating substance exchange between the brain and blood. We evaluated the effect of juvenile TBI (jTBI) on these processes by examining long-term alterations of BBB proteins, β-amyloid (Aβ) neuropathology, and cognitive changes. A controlled cortical impact was delivered to the parietal cortex of male rats at postnatal day 17, with behavioral studies and brain tissue evaluation at 60 days post-injury (dpi). Immunoglobulin G extravasation was unchanged, and jTBI animals had higher levels of tight-junction protein claudin 5 versus shams, suggesting the absence of BBB disruption. However, decreased P-glycoprotein (P-gp) on cortical blood vessels indicates modifications of BBB properties. In parallel, we observed higher levels of endogenous rodent Aβ in several brain regions of the jTBI group versus shams. In addition at 60 dpi, jTBI animals displayed systematic search strategies rather than relying on spatial memory during the water maze. Together, these alterations to the BBB phenotype after jTBI may contribute to the accumulation of toxic products, which in turn may induce cognitive differences and ultimately accelerate brain aging.

  6. Exposure to cold and draught, alcohol consumption, and the NS-phenotype are associated with chronic bronchitis: an epidemiological investigation of 3387 men aged 53-75 years: the Copenhagen Male Study.

    PubMed

    Suadicani, P; Hein, H O; Meyer, H W; Gyntelberg, F

    2001-03-01

    This study was performed to estimate the strength of association between chronic bronchitis and lifetime exposure to occupational factors, current lifestyle, and the NS-phenotype in the MNS blood group among middle aged and elderly men. The study was carried out within the frameworks of the Copenhagen Male Study. Of 3387 men 3331 men with a mean age of 63 (range 53-75) years could be classified by prevalence of chronic bronchitis. As well as the completion of a large questionnaire on health, lifestyle, and working conditions, all participants had a thorough examination, including measurements of height and weight and blood pressure and a venous blood sample was taken for the measurement of serum cotinine and MNS typing; 16.5% of the men had the NS-phenotype. Chronic bronchitis was defined as cough and phlegm lasting 3 months or more for at least 2 years; 14.6% had chronic bronchitis. Smoking and smoke inhalation were the factors most strongly associated with prevalence of chronic bronchitis. There were three major new findings: (a) long term (>5 years) occupational exposure to cold and draught was associated with a significantly increased prevalence of chronic bronchitis; compared with others, and adjusted for confounders, the odds ratio (OR) with 95% confidence interval (95% CI) was 1.4 (1.1 to 1.7), p=0.004; (b) a significant J shaped association existed between alcohol use and bronchitis, p<0.001, with the lowest prevalence found among moderate users; (c) a significant gene by environment association existed between smoking and the NS-phenotype in the MNS blood group; only among smokers was the NS-phenotype associated with a significantly decreased risk of chronic bronchitis, OR 0.67 (0.47-0.97), p=0.02. Other well known associations between dust, fumes, and even exposure to solvents and bronchitis were confirmed. The results emphasise the multifactorial nature of chronic bronchitis, and show some hitherto unrecognised associations between cold and draught

  7. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders.

    PubMed

    Wolff, Markus; Johannesen, Katrine M; Hedrich, Ulrike B S; Masnada, Silvia; Rubboli, Guido; Gardella, Elena; Lesca, Gaetan; Ville, Dorothée; Milh, Mathieu; Villard, Laurent; Afenjar, Alexandra; Chantot-Bastaraud, Sandra; Mignot, Cyril; Lardennois, Caroline; Nava, Caroline; Schwarz, Niklas; Gérard, Marion; Perrin, Laurence; Doummar, Diane; Auvin, Stéphane; Miranda, Maria J; Hempel, Maja; Brilstra, Eva; Knoers, Nine; Verbeek, Nienke; van Kempen, Marjan; Braun, Kees P; Mancini, Grazia; Biskup, Saskia; Hörtnagel, Konstanze; Döcker, Miriam; Bast, Thomas; Loddenkemper, Tobias; Wong-Kisiel, Lily; Baumeister, Friedrich M; Fazeli, Walid; Striano, Pasquale; Dilena, Robertino; Fontana, Elena; Zara, Federico; Kurlemann, Gerhard; Klepper, Joerg; Thoene, Jess G; Arndt, Daniel H; Deconinck, Nicolas; Schmitt-Mechelke, Thomas; Maier, Oliver; Muhle, Hiltrud; Wical, Beverly; Finetti, Claudio; Brückner, Reinhard; Pietz, Joachim; Golla, Günther; Jillella, Dinesh; Linnet, Karen M; Charles, Perrine; Moog, Ute; Õiglane-Shlik, Eve; Mantovani, John F; Park, Kristen; Deprez, Marie; Lederer, Damien; Mary, Sandrine; Scalais, Emmanuel; Selim, Laila; Van Coster, Rudy; Lagae, Lieven; Nikanorova, Marina; Hjalgrim, Helle; Korenke, G Christoph; Trivisano, Marina; Specchio, Nicola; Ceulemans, Berten; Dorn, Thomas; Helbig, Katherine L; Hardies, Katia; Stamberger, Hannah; de Jonghe, Peter; Weckhuysen, Sarah; Lemke, Johannes R; Krägeloh-Mann, Ingeborg; Helbig, Ingo; Kluger, Gerhard; Lerche, Holger; Møller, Rikke S

    2017-05-01

    Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells-together with data from the literature-suggest that

  8. Age-dependent increase in ortho-tyrosine and methionine sulfoxide in human skin collagen is not accelerated in diabetes. Evidence against a generalized increase in oxidative stress in diabetes.

    PubMed Central

    Wells-Knecht, M C; Lyons, T J; McCance, D R; Thorpe, S R; Baynes, J W

    1997-01-01

    The glycoxidation products Nepsilon-(carboxymethyl)lysine and pentosidine increase in skin collagen with age and at an accelerated rate in diabetes. Their age-adjusted concentrations in skin collagen are correlated with the severity of diabetic complications. To determine the relative roles of increased glycation and/or oxidation in the accelerated formation of glycoxidation products in diabetes, we measured levels of amino acid oxidation products, distinct from glycoxidative modifications of amino acids, as independent indicators of oxidative stress and damage to collagen in aging and diabetes. We show that ortho-tyrosine and methionine sulfoxide are formed in concert with Nepsilon-(carboxymethyl)lysine and pentosidine during glycoxidation of collagen in vitro, and that they also increase with age in human skin collagen. The age-adjusted levels of these oxidized amino acids in collagen was the same in diabetic and nondiabetic subjects, arguing that diabetes per se does not cause an increase in oxidative stress or damage to extracellular matrix proteins. These results provide evidence for an age-dependent increase in oxidative damage to collagen and support previous conclusions that the increase in glycoxidation products in skin collagen in diabetes can be explained by the increase in glycemia alone, without invoking a generalized, diabetes-dependent increase in oxidative stress. PMID:9259583

  9. Aging Research Using Mouse Models

    PubMed Central

    Ackert-Bicknell, Cheryl L.; Anderson, Laura; Sheehan, Susan; Hill, Warren G.; Chang, Bo; Churchill, Gary A.; Chesler, Elissa J.; Korstanje, Ron; Peters, Luanne L.

    2015-01-01

    Despite the dramatic increase in human lifespan over the past century, there remains pronounced variability in “health-span”, or the period of time in which one is generally healthy and free of disease. Much of the variability in health-span and lifespan is thought to be genetic in origin. Understanding the genetic mechanisms of aging and identifying ways to boost longevity is a primary goal in aging research. Here, we describe a pipeline of phenotypic assays for assessing mouse models of aging. This pipeline includes behavior/cognition testing, body composition analysis, and tests of kidney function, hematopoiesis, immune function and physical parameters. We also describe study design methods for assessing lifespan and health-span, and other important considerations when conducting aging research in the laboratory mouse. The tools and assays provided can assist researchers with understanding the correlative relationships between age-associated phenotypes and, ultimately, the role of specific genes in the aging process. PMID:26069080

  10. Decreased proteasomal function accelerates cigarette smoke-induced pulmonary emphysema in mice.

    PubMed

    Yamada, Yosuke; Tomaru, Utano; Ishizu, Akihiro; Ito, Tomoki; Kiuchi, Takayuki; Ono, Ayako; Miyajima, Syota; Nagai, Katsura; Higashi, Tsunehito; Matsuno, Yoshihiro; Dosaka-Akita, Hirotoshi; Nishimura, Masaharu; Miwa, Soichi; Kasahara, Masanori

    2015-06-01

    Chronic obstructive pulmonary disease (COPD) is a disease common in elderly people, characterized by progressive destruction of lung parenchyma and chronic inflammation of the airways. The pathogenesis of COPD remains unclear, but recent studies suggest that oxidative stress-induced apoptosis in alveolar cells contributes to emphysematous lung destruction. The proteasome is a multicatalytic enzyme complex that plays a critical role in proteostasis by rapidly destroying misfolded and modified proteins generated by oxidative and other stresses. Proteasome activity decreases with aging in many organs including lungs, and an age-related decline in proteasomal function has been implicated in various age-related pathologies. However, the role of the proteasome system in the pathogenesis of COPD has not been investigated. Recently, we have established a transgenic (Tg) mouse model with decreased proteasomal chymotrypsin-like activity, showing age-related phenotypes. Using this model, we demonstrate here that decreased proteasomal function accelerates cigarette smoke (CS)-induced pulmonary emphysema. CS-exposed Tg mice showed remarkable airspace enlargement and increased foci of inflammation compared with wild-type controls. Importantly, apoptotic cells were found in the alveolar walls of the affected lungs. Impaired proteasomal activity also enhanced apoptosis in cigarette smoke extract (CSE)-exposed fibroblastic cells derived from mice and humans in vitro. Notably, aggresome formation and prominent nuclear translocation of apoptosis-inducing factor were observed in CSE-exposed fibroblastic cells isolated from Tg mice. Collective evidence suggests that CS exposure and impaired proteasomal activity coordinately enhance apoptotic cell death in the alveolar walls that may be involved in the development and progression of emphysema in susceptible individuals such as the elderly.

  11. Phenotypes determined by cluster analysis in severe or difficult-to-treat asthma.

    PubMed

    Schatz, Michael; Hsu, Jin-Wen Y; Zeiger, Robert S; Chen, Wansu; Dorenbaum, Alejandro; Chipps, Bradley E; Haselkorn, Tmirah

    2014-06-01

    Asthma phenotyping can facilitate understanding of disease pathogenesis and potential targeted therapies. To further characterize the distinguishing features of phenotypic groups in difficult-to-treat asthma. Children ages 6-11 years (n = 518) and adolescents and adults ages ≥12 years (n = 3612) with severe or difficult-to-treat asthma from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study were evaluated in this post hoc cluster analysis. Analyzed variables included sex, race, atopy, age of asthma onset, smoking (adolescents and adults), passive smoke exposure (children), obesity, and aspirin sensitivity. Cluster analysis used the hierarchical clustering algorithm with the Ward minimum variance method. The results were compared among clusters by χ(2) analysis; variables with significant (P < .05) differences among clusters were considered as distinguishing feature candidates. Associations among clusters and asthma-related health outcomes were assessed in multivariable analyses by adjusting for socioeconomic status, environmental exposures, and intensity of therapy. Five clusters were identified in each age stratum. Sex, atopic status, and nonwhite race were distinguishing variables in both strata; passive smoke exposure was distinguishing in children and aspirin sensitivity in adolescents and adults. Clusters were not related to outcomes in children, but 2 adult and adolescent clusters distinguished by nonwhite race and aspirin sensitivity manifested poorer quality of life (P < .0001), and the aspirin-sensitive cluster experienced more frequent asthma exacerbations (P < .0001). Distinct phenotypes appear to exist in patients with severe or difficult-to-treat asthma, which is related to outcomes in adolescents and adults but not in children. The study of the therapeutic implications of these phenotypes is warranted. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights

  12. X-linked retinoschisis: RS1 mutation severity and age affect the ERG phenotype in a cohort of 68 affected male subjects.

    PubMed

    Bowles, Kristen; Cukras, Catherine; Turriff, Amy; Sergeev, Yuri; Vitale, Susan; Bush, Ronald A; Sieving, Paul A

    2011-11-29

    To assess the effect of age and RS1 mutation on the phenotype of X-linked retinoschisis (XLRS) subjects using the clinical electroretinogram (ERG) in a cross-sectional analysis. Sixty-eight XLRS males 4.5 to 55 years of age underwent genotyping, and the retinoschisis (RS1) mutations were classified as less severe (27 subjects) or more severe (41 subjects) based on the putative impact on the protein. ERG parameters of retinal function were analyzed by putative mutation severity with age as a continuous variable. The a-wave amplitude remained greater than the lower limit of normal (mean, -2 SD) for 72% of XLRS males and correlated with neither age nor mutation class. However, b-wave and b/a-ratio amplitudes were significantly lower in the more severe than in the less severe mutation groups and in older than in younger subjects. Subjects up to 10 years of age with more severe RS1 mutations had significantly greater b-wave amplitudes and faster a-wave trough implicit times than older subjects in this group. RS1 mutation putative severity and age both had significant effects on retinal function in XLRS only in the severe mutation group, as judged by ERG analysis of the b-wave amplitude and the b/a-ratio, whereas the a-wave amplitude remained normal in most. A new observation was that increasing age (limited to those aged 55 and younger) caused a significant delay in XLRS b-wave onset (i.e., a-wave implicit time), even for those who retained considerable b-wave amplitudes. The delayed b-wave onset suggested that dysfunction of the photoreceptor synapse or of bipolar cells increases with age of XLRS subjects.

  13. Wolfram Syndrome: New Mutations, Different Phenotype

    PubMed Central

    Pasquali, Lorenzo; Lugani, Francesca; Perri, Katia; Russo, Chiara; Tallone, Ramona; Ghiggeri, Gian Marco; Lorini, Renata; d'Annunzio, Giuseppe

    2012-01-01

    Background Wolfram Syndrome (WS) is an autosomal recessive neurodegenerative disorder characterized by Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness identified by the acronym “DIDMOAD”. The WS gene, WFS1, encodes a transmembrane protein called Wolframin, which recent evidence suggests may serve as a novel endoplasmic reticulum calcium channel in pancreatic β-cells and neurons. WS is a rare disease, with an estimated prevalence of 1/550.000 children, with a carrier frequency of 1/354. The aim of our study was to determine the genotype of WS patients in order to establish a genotype/phenotype correlation. Methodology/Principal Findings We clinically evaluated 9 young patients from 9 unrelated families (6 males, 3 females). Basic criteria for WS clinical diagnosis were coexistence of insulin-treated diabetes mellitus and optic atrophy occurring before 15 years of age. Genetic analysis for WFS1 was performed by direct sequencing. Molecular sequencing revealed 5 heterozygous compound and 3 homozygous mutations. All of them were located in exon 8, except one in exon 4. In one proband only an heterozygous mutation (A684V) was found. Two new variants c.2663 C>A and c.1381 A>C were detected. Conclusions/Significance Our study increases the spectrum of WFS1 mutations with two novel variants. The male patient carrying the compound mutation [c.1060_1062delTTC]+[c.2663 C>A] showed the most severe phenotype: diabetes mellitus, optic atrophy (visual acuity 5/10), deafness with deep auditory bilaterally 8000 Hz, diabetes insipidus associated to reduced volume of posterior pituitary and pons. He died in bed at the age of 13 years. The other patient carrying the compound mutation [c.409_424dup16]+[c.1381 A>C] showed a less severe phenotype (DM, OA). PMID:22238590

  14. Phenotypic assortment in wild primate networks: implications for the dissemination of information.

    PubMed

    Carter, Alecia J; Lee, Alexander E G; Marshall, Harry H; Ticó, Miquel Torrents; Cowlishaw, Guy

    2015-05-01

    Individuals' access to social information can depend on their social network. Homophily-a preference to associate with similar phenotypes-may cause assortment within social networks that could preclude information transfer from individuals who generate information to those who would benefit from acquiring it. Thus, understanding phenotypic assortment may lead to a greater understanding of the factors that could limit the transfer of information between individuals. We tested whether there was assortment in wild baboon (Papio ursinus) networks, using data collected from two troops over 6 years for six phenotypic traits-boldness, age, dominance rank, sex and the propensity to generate/exploit information-using two methods for defining a connection between individuals-time spent in proximity and grooming. Our analysis indicated that assortment was more common in grooming than proximity networks. In general, there was homophily for boldness, age, rank and the propensity to both generate and exploit information, but heterophily for sex. However, there was considerable variability both between troops and years. The patterns of homophily we observed for these phenotypes may impede information transfer between them. However, the inconsistency in the strength of assortment between troops and years suggests that the limitations to information flow may be quite variable.

  15. The anti-aging effects of LW-AFC via correcting immune dysfunctions in senescence accelerated mouse resistant 1 (SAMR1) strain.

    PubMed

    Wang, Jianhui; Cheng, Xiaorui; Zhang, Xiaorui; Cheng, Junping; Xu, Yiran; Zeng, Ju; Zhou, Wenxia; Zhang, Yongxiang

    2016-05-10

    Although there were considerable advances in the anti-aging medical field, it is short of therapeutic drug for anti-aging. Mounting evidence indicates that the immunosenescence is the key physiopathological mechanism of aging. This study showed the treatment of LW-AFC, an herbal medicine, decreased the grading score of senescence, increased weight, prolonged average life span and ameliorated spatial memory impairment in 12- and 24-month-old senescence accelerated mouse resistant 1 (SAMR1) strain. And these anti-aging effects of LW-AFC were more excellent than melatonin. The administration of LW-AFC enhanced ConA- and LPS-induced splenocyte proliferation in aged SAMR1 mice. The treatment of LW-AFC not only reversed the decreased the proportions of helper T cells, suppressor T cells and B cells, the increased regulatory T cells in the peripheral blood of old SAMR1 mice, but also could modulate the abnormal secretion of IL-1β, IL-2, IL-6, IL-17, IL-23, GM-CSF, IFN-γ, TNF-α, TNF-β, RANTES, eotaxin, MCP-1, IL-4, IL-5, IL-10 and G-CSF. These data indicated that LW-AFC reversed the immunosenescence status by restoring immunodeficiency and decreasing chronic inflammation and suggested LW-AFC may be an effective anti-aging agent.

  16. Pilot evaluation of short-term changes in macular pigment and retinal sensitivity in different phenotypes of early age-related macular degeneration after carotenoid supplementation.

    PubMed

    Corvi, Federico; Souied, Eric H; Falfoul, Yousra; Georges, Anouk; Jung, Camille; Querques, Lea; Querques, Giuseppe

    2017-06-01

    To investigate the response of carotenoid supplementation in different phenotypes of early age-related macular degeneration (AMD) by measuring macular pigment optical density (MPOD) and retinal sensitivity. Consecutive patients with only medium/large drusen and only reticular pseudodrusen (RPD) and age-matched and sex-matched controls were enrolled. At baseline, participants underwent a complete ophthalmological examination including measurement of best-corrected visual acuity (BCVA), MPOD and retinal sensitivity. Patients were put on vitamin supplementation (lutein 10 mg/day, zeaxanthin 2 mg/day) and 3 months later underwent a repeated ophthalmological examination. Twenty patients with medium/large drusen, 19 with RPD and 15 control subjects were included. At baseline, in controls, mean MPOD and BCVA were significantly higher compared with RPD (p=0.001 and p=0.01) but similar to medium/large drusen (p=0.9 and p=0.4). Mean retinal sensitivity was significantly higher in controls compared with RPD and medium/large drusen (for all p<0.0001). After 3 months of carotenoid supplementation the mean MPOD significantly increased in RPD (p=0.002), thus showing no more difference compared with controls (p=0.3); no significant changes were found in mean retinal sensitivity and BCVA (p=0.3 and p=0.7). Medium/large drusen did not show significant changes on MPOD, retinal sensitivity and BCVA (p=0.5, p=0.7 and p=0.7, respectively). Patients with early AMD, especially RPD phenotype, show lower macular sensitivity and MPOD than controls. After supplementation, MPOD significantly increased in RPD. These results suggest different pathophysiology for RPD as compared with medium/large drusen and may open new ways to identifying further therapeutic targets in this phenotype of early AMD. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  17. Prognostics of Power Mosfets Under Thermal Stress Accelerated Aging Using Data-Driven and Model-Based Methodologies

    NASA Technical Reports Server (NTRS)

    Celaya, Jose; Saxena, Abhinav; Saha, Sankalita; Goebel, Kai F.

    2011-01-01

    An approach for predicting remaining useful life of power MOSFETs (metal oxide field effect transistor) devices has been developed. Power MOSFETs are semiconductor switching devices that are instrumental in electronics equipment such as those used in operation and control of modern aircraft and spacecraft. The MOSFETs examined here were aged under thermal overstress in a controlled experiment and continuous performance degradation data were collected from the accelerated aging experiment. Dieattach degradation was determined to be the primary failure mode. The collected run-to-failure data were analyzed and it was revealed that ON-state resistance increased as die-attach degraded under high thermal stresses. Results from finite element simulation analysis support the observations from the experimental data. Data-driven and model based prognostics algorithms were investigated where ON-state resistance was used as the primary precursor of failure feature. A Gaussian process regression algorithm was explored as an example for a data-driven technique and an extended Kalman filter and a particle filter were used as examples for model-based techniques. Both methods were able to provide valid results. Prognostic performance metrics were employed to evaluate and compare the algorithms.

  18. Aging curve of neuromotor function by pronation and supination of forearms using three-dimensional wireless acceleration and angular velocity sensors.

    PubMed

    Kaneko, M; Okui, H; Hirakawa, G; Ishinishi, H; Katayama, Y; Iramina, K

    2012-01-01

    We have developed an evaluation system for pronation and supination of forearms. The motion of pronation and supination of the forearm is used as a diagnosis method of developmental disability, etc. However, this diagnosis method has a demerit in which diagnosis results between doctors are not consistent. It is hoped that a more quantitative and simple evaluation method is established. Moreover it is hoped a diagnostic criteria obtained from healthy subjects can be established to diagnose developmental disorder patients. We developed a simple and portable evaluation system for pronation and supination of forearms. Three-dimensional wireless acceleration and angular velocity sensors are used for this system. In this study, pronation and supination of forearms of 570 subjects (subjects aged 6-12, 21-100) were examined. We could obtain aging curves in the neuromotor function of pronation and supination. These aging curves obtained by our developed system, has the potential to become diagnostic criteria for a developmental disability, etc.

  19. Physical exercise during muscle regeneration improves recovery of the slow/oxidative phenotype.

    PubMed

    Koulmann, Nathalie; Richard-Bulteau, Hélène; Crassous, Brigitte; Serrurier, Bernard; Pasdeloup, Marielle; Bigard, Xavier; Banzet, Sébastien

    2017-01-01

    As skeletal muscle mass recovery after extensive injury is improved by contractile activity, we explored whether concomitant exercise accelerates recovery of the contractile and metabolic phenotypes after muscle injury. After notexin-induced degeneration of a soleus muscle, Wistar rats were assigned to active (running exercise) or sedentary groups. Myosin heavy chains (MHC), metabolic enzymes, and calcineurin were studied during muscle regeneration at different time points. The mature MHC profile recovered earlier in active rats (21 days after injury) than in sedentary rats (42 days). Calcineurin was higher in the active degenerated than in the sedentary degenerated muscles at day 14. Citrate synthase and total lactate dehydrogenase (LDH) activity decreased after injury and were similarly recovered in both active and sedentary groups at 14 or 42 days, respectively. H-LDH isozyme activity recovered earlier in the active rats. Exercise improved recovery of the slow/oxidative phenotype after soleus muscle injury. Muscle Nerve 55: 91-100, 2017. © 2016 Wiley Periodicals, Inc.

  20. Modulation of the phenolic composition and colour of red wines subjected to accelerated ageing by controlling process variables.

    PubMed

    González-Sáiz, J M; Esteban-Díez, I; Rodríguez-Tecedor, S; Pérez-Del-Notario, N; Arenzana-Rámila, I; Pizarro, C

    2014-12-15

    The aim of the present work was to evaluate the effect of the main factors conditioning accelerated ageing processes (oxygen dose, chip dose, wood origin, toasting degree and maceration time) on the phenolic and chromatic profiles of red wines by using a multivariate strategy based on experimental design methodology. The results obtained revealed that the concentrations of monomeric anthocyanins and flavan-3-ols could be modified through the application of particular experimental conditions. This fact was particularly remarkable since changes in phenolic profile were closely linked to changes observed in chromatic parameters. The main strength of this study lies in the possibility of using its conclusions as a basis to make wines with specific colour properties based on quality criteria. To our knowledge, the influence of such a large number of alternative ageing parameters on wine phenolic composition and chromatic attributes has not been studied previously using a comprehensive experimental design methodology. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Accelerated Reader: Evaluation Report and Executive Summary

    ERIC Educational Resources Information Center

    Gorard, Stephen; Siddiqui, Nadia; See, Beng Huat

    2015-01-01

    Accelerated Reader (AR) is a whole-group reading management and monitoring program that aims to foster the habit of independent reading among primary and early secondary age pupils. The internet-based software initially screens pupils according to their reading levels, and suggests books that match their reading age and reading interest. Pupils…

  2. Accelerator system and method of accelerating particles

    NASA Technical Reports Server (NTRS)

    Wirz, Richard E. (Inventor)

    2010-01-01

    An accelerator system and method that utilize dust as the primary mass flux for generating thrust are provided. The accelerator system can include an accelerator capable of operating in a self-neutralizing mode and having a discharge chamber and at least one ionizer capable of charging dust particles. The system can also include a dust particle feeder that is capable of introducing the dust particles into the accelerator. By applying a pulsed positive and negative charge voltage to the accelerator, the charged dust particles can be accelerated thereby generating thrust and neutralizing the accelerator system.

  3. Divergent sensory phenotypes in nonspecific arm pain: comparisons with cervical radiculopathy.

    PubMed

    Moloney, Niamh; Hall, Toby; Doody, Catherine

    2015-02-01

    To investigate whether distinct sensory phenotypes were identifiable in individuals with nonspecific arm pain (NSAP) and whether these differed from those in people with cervical radiculopathy. A secondary question considered whether the frequency of features of neuropathic pain, kinesiophobia, high pain ratings, hyperalgesia, and allodynia differed according to subgroups of sensory phenotypes. Cross-sectional study. Higher education institution. Forty office workers with NSAP, 17 people with cervical radiculopathy, and 40 age- and sex-matched healthy controls (N=97). Not applicable. Participants were assessed using quantitative sensory testing (QST) comprising thermal and vibration detection thresholds and thermal and pressure pain thresholds; clinical examination; and relevant questionnaires. Sensory phenotypes were identified for each individual in the patient groups using z-score transformation of the QST data. Individuals with NSAP and cervical radiculopathy present with a spectrum of sensory abnormalities; a dominant sensory phenotype was not identifiable in individuals with NSAP. No distinct pattern between clinical features and questionnaire results across sensory phenotypes was identified in either group. When considering sensory phenotypes, neither individuals with NSAP nor individuals with cervical radiculopathy should be considered homogeneous. Therefore, people with either condition may warrant different intervention approaches according to their individual sensory phenotype. Issues relating to the clinical identification of sensory hypersensitivity and the validity of QST are highlighted. Copyright © 2015 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

  4. Emergence of the P2 Phenotype in Pseudomonas aeruginosa PAO1 Strains Involves Various Mutations in mexT or mexF

    PubMed Central

    Luong, Preston M.; Shogan, Benjamin D.; Zaborin, Alexander; Belogortseva, Natalia; Shrout, Joshua D.

    2014-01-01

    We recently demonstrated that Pseudomonas aeruginosa PAO1 undergoes a pronounced phenotypic change when introduced into the intestines of rats during surgical injury. Recovered strains displayed a specific phenotype (termed the P2 phenotype) characterized by altered pyocyanin production, high collagenase activity, high swarming motility, low resistance to chloramphenicol, and increased killing of Caenorhabditis elegans compared to the inoculating strain (termed the P1 phenotype). The aims of this study were to characterize the differences between the P. aeruginosa P1 and P2 phenotypes in quorum sensing and competitiveness. We then determined the presence of the P2 phenotype among PAO1 strains from various laboratories. Results demonstrated that P2 cells display accelerated growth during early exponential phase and early activation of quorum-sensing systems and overcome the growth of P1 cells in a mixed population. Among eight PAO1 strains obtained from different laboratories, four exhibited the P2 phenotype. Of 27 mutants analyzed from the P. aeruginosa MPAO1 transposon library, 25 displayed P2 phenotypes. The P2 phenotype in both cases correlated with a lack of expression of mexE or mexF due to mutations in mexT and mexF genes. In summary, strains possessing the P2 phenotype are distributed among PAO1 strains commonly used across a variety of research laboratories. Genetically, they are characterized by various mutations in mexT or mexF. PMID:24244000

  5. Histone methylation and aging: Lessons learned from model systems

    PubMed Central

    McCauley, Brenna S.; Dang, Weiwei

    2014-01-01

    Aging induces myriad cellular and, ultimately, physiological changes that cause a decline in an organism's functional capabilities. Although the aging process and pathways that regulate it have been extensively studied, only in the last decade have we begun to appreciate that dynamic histone methylation may contribute to this process. In this review, we discuss recent work implicating histone methylation in aging. Loss of certain histone methyltransferases and demethylases changes lifespan in invertebrates, and alterations in histone methylation in aged organisms regulate lifespan and aging phenotypes, including oxidative stress-induced hormesis in yeast, insulin signaling in Caenorhabiditis elegans and mammals, and the senescence-associated secretory phenotype in mammals. In all cases where histone methylation has been shown to impact aging and aging phenotypes, it does so by regulating transcription, suggesting that this is a major mechanism of its action in this context. Histone methylation additionally regulates or is regulated by other cellular pathways that contribute to or combat aging. Given the numerous processes that regulate aging and histone methylation, and are in turn regulated by them, the role of histone methylation in aging is almost certainly underappreciated. PMID:24859460

  6. Phenotypic characteristics of Alzheimer patients carrying an ABCA7 mutation.

    PubMed

    Van den Bossche, Tobi; Sleegers, Kristel; Cuyvers, Elise; Engelborghs, Sebastiaan; Sieben, Anne; De Roeck, Arne; Van Cauwenberghe, Caroline; Vermeulen, Steven; Van den Broeck, Marleen; Laureys, Annelies; Peeters, Karin; Mattheijssens, Maria; Vandenbulcke, Mathieu; Vandenberghe, Rik; Martin, Jean-Jacques; De Deyn, Peter P; Cras, Patrick; Van Broeckhoven, Christine

    2016-06-07

    To generate a clinical and pathologic phenotype of patients carrying rare loss-of-function mutations in ABCA7, identified in a Belgian Alzheimer patient cohort and in an autosomal dominant family. We performed a retrospective review of available data records, medical records, results of CSF analyses and neuroimaging studies, and neuropathology data. The mean onset age of the mutation carriers (n = 22) was 73.4 ± 8.4 years with a wide age range of 36 (54-90) years, which was independent of APOE genotype and cerebrovascular disease. The mean disease duration was 5.7 ± 3.0 years (range 2-12 years). A positive family history was recorded for 10 carriers (45.5%). All patient carriers except one presented with memory complaints. The 4 autopsied brains showed typical immunohistochemical changes of late-onset Alzheimer disease. All patients carrying a loss-of-function mutation in ABCA7 exhibited a classical Alzheimer disease phenotype, though with a striking wide onset age range, suggesting the influence of unknown modifying factors. © 2016 American Academy of Neurology.

  7. Phenotypic characteristics of Alzheimer patients carrying an ABCA7 mutation

    PubMed Central

    Van den Bossche, Tobi; Sleegers, Kristel; Cuyvers, Elise; Engelborghs, Sebastiaan; Sieben, Anne; De Roeck, Arne; Van Cauwenberghe, Caroline; Vermeulen, Steven; Van den Broeck, Marleen; Laureys, Annelies; Peeters, Karin; Mattheijssens, Maria; Vandenbulcke, Mathieu; Vandenberghe, Rik; Martin, Jean-Jacques; De Deyn, Peter P.; Cras, Patrick

    2016-01-01

    Objective: To generate a clinical and pathologic phenotype of patients carrying rare loss-of-function mutations in ABCA7, identified in a Belgian Alzheimer patient cohort and in an autosomal dominant family. Methods: We performed a retrospective review of available data records, medical records, results of CSF analyses and neuroimaging studies, and neuropathology data. Results: The mean onset age of the mutation carriers (n = 22) was 73.4 ± 8.4 years with a wide age range of 36 (54–90) years, which was independent of APOE genotype and cerebrovascular disease. The mean disease duration was 5.7 ± 3.0 years (range 2–12 years). A positive family history was recorded for 10 carriers (45.5%). All patient carriers except one presented with memory complaints. The 4 autopsied brains showed typical immunohistochemical changes of late-onset Alzheimer disease. Conclusions: All patients carrying a loss-of-function mutation in ABCA7 exhibited a classical Alzheimer disease phenotype, though with a striking wide onset age range, suggesting the influence of unknown modifying factors. PMID:27037232

  8. Phenotypic differences between oral and skin fibroblasts in wound contraction and growth factor expression.

    PubMed

    Shannon, Diane B; McKeown, Scott T W; Lundy, Fionnuala T; Irwin, Chris R

    2006-01-01

    Wounds of the oral mucosa heal in an accelerated fashion with reduced scarring compared with cutaneous wounds. The differences in healing outcome between oral mucosa and skin could be because of phenotypic differences between the respective fibroblast populations. This study compared paired mucosal and dermal fibroblasts in terms of collagen gel contraction, alpha-smooth muscle actin expression (alpha-SMA), and production of the epithelial growth factors: keratinocyte growth factor (KGF) and hepatocyte growth factor/scatter factor (HGF). The effects of transforming growth factor -beta1 and -beta3 on each parameter were also determined. Gel contraction in floating collagen lattices was determined over a 7-day period. alpha-SMA expression by fibroblasts was determined by Western blotting. KGF and HGF expression were determined by an enzyme-linked immunosorbent assay. Oral fibroblasts induced accelerated collagen gel contraction, yet surprisingly expressed lower levels of alpha-SMA. Oral cells also produced significantly greater levels of both KGF and HGF than their dermal counterparts. Transforming growth factor-beta1 and -beta3, over the concentration range of 0.1-10 ng/mL, had similar effects on cell function, stimulating both gel contraction and alpha-SMA production, but inhibiting KGF and HGF production by both cell types. These data indicate phenotypic differences between oral and dermal fibroblasts that may well contribute to the differences in healing outcome between these two tissues.

  9. Characterization of Rod Function Phenotypes Across a Range of Age-Related Macular Degeneration Severities and Subretinal Drusenoid Deposits

    PubMed Central

    Flynn, Oliver J.; Cukras, Catherine A.; Jeffrey, Brett G.

    2018-01-01

    Purpose To examine spatial changes in rod-mediated function in relationship to local structural changes across the central retina in eyes with a spectrum of age-related macular degeneration (AMD) disease severity. Methods Participants were categorized into five AMD severity groups based on fundus features. Scotopic thresholds were measured at 14 loci spanning ±18° along the vertical meridian from one eye of each of 42 participants (mean = 71.7 ± 9.9 years). Following a 30% bleach, dark adaptation was measured at eight loci (±12°). Rod intercept time (RIT) was defined from the time to detect a −3.1 log cd/m2 stimulus. RITslope was defined from the linear fit of RIT with decreasing retinal eccentricity. The presence of subretinal drusenoid deposits (SDD), ellipsoid (EZ) band disruption, and drusen at the test loci was evaluated using optical coherence tomography. Results Scotopic thresholds indicated greater rod function loss in the macula, which correlated with increasing AMD group severity. RITslope, which captures the spatial change in the rate of dark adaptation, increased with AMD severity (P < 0.0001). Three rod function phenotypes emerged: RF1, normal rod function; RF2, normal scotopic thresholds but slowed dark adaptation; and RF3, elevated scotopic thresholds with slowed dark adaptation. Dark adaptation was slowed at all loci with SDD or EZ band disruption, and at 32% of loci with no local structural changes. Conclusions Three rod function phenotypes were defined from combined measurement of scotopic threshold and dark adaptation. Spatial changes in dark adaptation across the macula were captured with RITslope, which may be a useful outcome measure for functional studies of AMD. PMID:29847647

  10. Characterization of Rod Function Phenotypes Across a Range of Age-Related Macular Degeneration Severities and Subretinal Drusenoid Deposits.

    PubMed

    Flynn, Oliver J; Cukras, Catherine A; Jeffrey, Brett G

    2018-05-01

    To examine spatial changes in rod-mediated function in relationship to local structural changes across the central retina in eyes with a spectrum of age-related macular degeneration (AMD) disease severity. Participants were categorized into five AMD severity groups based on fundus features. Scotopic thresholds were measured at 14 loci spanning ±18° along the vertical meridian from one eye of each of 42 participants (mean = 71.7 ± 9.9 years). Following a 30% bleach, dark adaptation was measured at eight loci (±12°). Rod intercept time (RIT) was defined from the time to detect a -3.1 log cd/m2 stimulus. RITslope was defined from the linear fit of RIT with decreasing retinal eccentricity. The presence of subretinal drusenoid deposits (SDD), ellipsoid (EZ) band disruption, and drusen at the test loci was evaluated using optical coherence tomography. Scotopic thresholds indicated greater rod function loss in the macula, which correlated with increasing AMD group severity. RITslope, which captures the spatial change in the rate of dark adaptation, increased with AMD severity (P < 0.0001). Three rod function phenotypes emerged: RF1, normal rod function; RF2, normal scotopic thresholds but slowed dark adaptation; and RF3, elevated scotopic thresholds with slowed dark adaptation. Dark adaptation was slowed at all loci with SDD or EZ band disruption, and at 32% of loci with no local structural changes. Three rod function phenotypes were defined from combined measurement of scotopic threshold and dark adaptation. Spatial changes in dark adaptation across the macula were captured with RITslope, which may be a useful outcome measure for functional studies of AMD.

  11. Accelerated aging studies of UHMWPE. I. Effect of resin, processing, and radiation environment on resistance to mechanical degradation.

    PubMed

    Edidin, A A; Herr, M P; Villarraga, M L; Muth, J; Yau, S S; Kurtz, S M

    2002-08-01

    The resin and processing route have been identified as potential variables influencing the mechanical behavior, and hence the clinical performance, of ultra-high molecular weight polyethylene (UHMWPE) orthopedic components. Researchers have reported that components fabricated from 1900 resin may oxidize to a lesser extent than components fabricated from GUR resin during shelf aging after gamma sterilization in air. Conflicting reports on the oxidation resistance for 1900 raise the question of whether resin or manufacturing method, or an interaction between resin and manufacturing method, influences the mechanical behavior of UHMWPE. We conducted a series of accelerated aging studies (no aging, aging in oxygen or in nitrogen) to systematically examine the influence of resin (GUR or 1900), manufacturing method (bulk compression molding or extrusion), and sterilization method (none, in air, or in nitrogen) on the mechanical behavior of UHMWPE. The small punch testing technique was used to evaluate the mechanical behavior of the materials, and Fourier transform infrared spectroscopy was used to characterize the oxidation in selected samples. Our study showed that the sterilization environment, aging condition, and specimen location (surface or subsurface) significantly affected the mechanical behavior of UHMWPE. Each of the three polyethylenes evaluated seem to degrade according to a similar pathway after artificial aging in oxygen and gamma irradiation in air. The initial ability of the materials to exhibit post-yield strain hardening was significantly compromised by degradation. In general, there were only minor differences in the aging behavior of molded and extruded GUR 1050, whereas the molded 1900 material seemed to degrade slightly faster than either of the 1050 materials. Copyright 2002 Wiley Periodicals, Inc.

  12. Macrophage Differentiation in Normal and Accelerated Wound Healing.

    PubMed

    Kotwal, Girish J; Chien, Sufan

    2017-01-01

    Chronic wounds pose considerable public health challenges and burden. Wound healing is known to require the participation of macrophages, but mechanisms remain unclear. The M1 phenotype macrophages have a known scavenger function, but they also play multiple roles in tissue repair and regeneration when they transition to an M2 phenotype. Macrophage precursors (mononuclear cells/monocytes) follow the influx of PMN neutrophils into a wound during the natural wound-healing process, to become the major cells in the wound. Natural wound-healing process is a four-phase progression consisting of hemostasis, inflammation, proliferation, and remodeling. A lag phase of 3-6 days precedes the remodeling phase, which is characterized by fibroblast activation and finally collagen production. This normal wound-healing process can be accelerated by the intracellular delivery of ATP to wound tissue. This novel ATP-mediated acceleration arises due to an alternative activation of the M1 to M2 transition (macrophage polarization), a central and critical feature of the wound-healing process. This response is also characterized by an early increased release of pro-inflammatory cytokines (TNF, IL-1 beta, IL-6), a chemokine (MCP-1), an activation of purinergic receptors (a family of plasma membrane receptors found in almost all mammalian cells), and an increased production of platelets and platelet microparticles. These factors trigger a massive influx of macrophages, as well as in situ proliferation of the resident macrophages and increased synthesis of VEGFs. These responses are followed, in turn, by rapid neovascularization and collagen production by the macrophages, resulting in wound covering with granulation tissue within 24 h.

  13. Novel gene function revealed by mouse mutagenesis screens for models of age-related disease.

    PubMed

    Potter, Paul K; Bowl, Michael R; Jeyarajan, Prashanthini; Wisby, Laura; Blease, Andrew; Goldsworthy, Michelle E; Simon, Michelle M; Greenaway, Simon; Michel, Vincent; Barnard, Alun; Aguilar, Carlos; Agnew, Thomas; Banks, Gareth; Blake, Andrew; Chessum, Lauren; Dorning, Joanne; Falcone, Sara; Goosey, Laurence; Harris, Shelley; Haynes, Andy; Heise, Ines; Hillier, Rosie; Hough, Tertius; Hoslin, Angela; Hutchison, Marie; King, Ruairidh; Kumar, Saumya; Lad, Heena V; Law, Gemma; MacLaren, Robert E; Morse, Susan; Nicol, Thomas; Parker, Andrew; Pickford, Karen; Sethi, Siddharth; Starbuck, Becky; Stelma, Femke; Cheeseman, Michael; Cross, Sally H; Foster, Russell G; Jackson, Ian J; Peirson, Stuart N; Thakker, Rajesh V; Vincent, Tonia; Scudamore, Cheryl; Wells, Sara; El-Amraoui, Aziz; Petit, Christine; Acevedo-Arozena, Abraham; Nolan, Patrick M; Cox, Roger; Mallon, Anne-Marie; Brown, Steve D M

    2016-08-18

    Determining the genetic bases of age-related disease remains a major challenge requiring a spectrum of approaches from human and clinical genetics to the utilization of model organism studies. Here we report a large-scale genetic screen in mice employing a phenotype-driven discovery platform to identify mutations resulting in age-related disease, both late-onset and progressive. We have utilized N-ethyl-N-nitrosourea mutagenesis to generate pedigrees of mutagenized mice that were subject to recurrent screens for mutant phenotypes as the mice aged. In total, we identify 105 distinct mutant lines from 157 pedigrees analysed, out of which 27 are late-onset phenotypes across a range of physiological systems. Using whole-genome sequencing we uncover the underlying genes for 44 of these mutant phenotypes, including 12 late-onset phenotypes. These genes reveal a number of novel pathways involved with age-related disease. We illustrate our findings by the recovery and characterization of a novel mouse model of age-related hearing loss.

  14. Novel gene function revealed by mouse mutagenesis screens for models of age-related disease

    PubMed Central

    Potter, Paul K.; Bowl, Michael R.; Jeyarajan, Prashanthini; Wisby, Laura; Blease, Andrew; Goldsworthy, Michelle E.; Simon, Michelle M.; Greenaway, Simon; Michel, Vincent; Barnard, Alun; Aguilar, Carlos; Agnew, Thomas; Banks, Gareth; Blake, Andrew; Chessum, Lauren; Dorning, Joanne; Falcone, Sara; Goosey, Laurence; Harris, Shelley; Haynes, Andy; Heise, Ines; Hillier, Rosie; Hough, Tertius; Hoslin, Angela; Hutchison, Marie; King, Ruairidh; Kumar, Saumya; Lad, Heena V.; Law, Gemma; MacLaren, Robert E.; Morse, Susan; Nicol, Thomas; Parker, Andrew; Pickford, Karen; Sethi, Siddharth; Starbuck, Becky; Stelma, Femke; Cheeseman, Michael; Cross, Sally H.; Foster, Russell G.; Jackson, Ian J.; Peirson, Stuart N.; Thakker, Rajesh V.; Vincent, Tonia; Scudamore, Cheryl; Wells, Sara; El-Amraoui, Aziz; Petit, Christine; Acevedo-Arozena, Abraham; Nolan, Patrick M.; Cox, Roger; Mallon, Anne-Marie; Brown, Steve D. M.

    2016-01-01

    Determining the genetic bases of age-related disease remains a major challenge requiring a spectrum of approaches from human and clinical genetics to the utilization of model organism studies. Here we report a large-scale genetic screen in mice employing a phenotype-driven discovery platform to identify mutations resulting in age-related disease, both late-onset and progressive. We have utilized N-ethyl-N-nitrosourea mutagenesis to generate pedigrees of mutagenized mice that were subject to recurrent screens for mutant phenotypes as the mice aged. In total, we identify 105 distinct mutant lines from 157 pedigrees analysed, out of which 27 are late-onset phenotypes across a range of physiological systems. Using whole-genome sequencing we uncover the underlying genes for 44 of these mutant phenotypes, including 12 late-onset phenotypes. These genes reveal a number of novel pathways involved with age-related disease. We illustrate our findings by the recovery and characterization of a novel mouse model of age-related hearing loss. PMID:27534441

  15. Phenotypic switching in bacteria

    NASA Astrophysics Data System (ADS)

    Merrin, Jack

    Living matter is a non-equilibrium system in which many components work in parallel to perpetuate themselves through a fluctuating environment. Physiological states or functionalities revealed by a particular environment are called phenotypes. Transitions between phenotypes may occur either spontaneously or via interaction with the environment. Even in the same environment, genetically identical bacteria can exhibit different phenotypes of a continuous or discrete nature. In this thesis, we pursued three lines of investigation into discrete phenotypic heterogeneity in bacterial populations: the quantitative characterization of the so-called bacterial persistence, a theoretical model of phenotypic switching based on those measurements, and the design of artificial genetic networks which implement this model. Persistence is the phenotype of a subpopulation of bacteria with a reduced sensitivity to antibiotics. We developed a microfluidic apparatus, which allowed us to monitor the growth rates of individual cells while applying repeated cycles of antibiotic treatments. We were able to identify distinct phenotypes (normal and persistent) and characterize the stochastic transitions between them. We also found that phenotypic heterogeneity was present prior to any environmental cue such as antibiotic exposure. Motivated by the experiments with persisters, we formulated a theoretical model describing the dynamic behavior of several discrete phenotypes in a periodically varying environment. This theoretical framework allowed us to quantitatively predict the fitness of dynamic populations and to compare survival strategies according to environmental time-symmetries. These calculations suggested that persistence is a strategy used by bacterial populations to adapt to fluctuating environments. Knowledge of the phenotypic transition rates for persistence may provide statistical information about the typical environments of bacteria. We also describe a design of artificial

  16. Phenotype at diagnosis predicts recurrence rates in Crohn's disease.

    PubMed

    Wolters, F L; Russel, M G; Sijbrandij, J; Ambergen, T; Odes, S; Riis, L; Langholz, E; Politi, P; Qasim, A; Koutroubakis, I; Tsianos, E; Vermeire, S; Freitas, J; van Zeijl, G; Hoie, O; Bernklev, T; Beltrami, M; Rodriguez, D; Stockbrügger, R W; Moum, B

    2006-08-01

    In Crohn's disease (CD), studies associating phenotype at diagnosis and subsequent disease activity are important for patient counselling and health care planning. To calculate disease recurrence rates and to correlate these with phenotypic traits at diagnosis. A prospectively assembled uniformly diagnosed European population based inception cohort of CD patients was classified according to the Vienna classification for disease phenotype at diagnosis. Surgical and non-surgical recurrence rates throughout a 10 year follow up period were calculated. Multivariate analysis was performed to classify risk factors present at diagnosis for recurrent disease. A total of 358 were classified for phenotype at diagnosis, of whom 262 (73.2%) had a first recurrence and 113 patients (31.6%) a first surgical recurrence during the first 10 years after diagnosis. Patients with upper gastrointestinal disease at diagnosis had an excess risk of recurrence (hazard ratio 1.54 (95% confidence interval (CI) 1.13-2.10)) whereas age >/=40 years at diagnosis was protective (hazard ratio 0.82 (95% CI 0.70-0.97)). Colonic disease was a protective characteristic for resective surgery (hazard ratio 0.38 (95% CI 0.21-0.69)). More frequent resective surgical recurrences were reported from Copenhagen (hazard ratio 3.23 (95% CI 1.32-7.89)). A mild course of disease in terms of disease recurrence was observed in this European cohort. Phenotype at diagnosis had predictive value for disease recurrence with upper gastrointestinal disease being the most important positive predictor. A phenotypic North-South gradient in CD may be present, illustrated by higher surgery risks in some of the Northern European centres.

  17. Partial sleep deprivation activates the DNA damage response (DDR) and the senescence-associated secretory phenotype (SASP) in aged adult humans.

    PubMed

    Carroll, Judith E; Cole, Steven W; Seeman, Teresa E; Breen, Elizabeth C; Witarama, Tuff; Arevalo, Jesusa M G; Ma, Jeffrey; Irwin, Michael R

    2016-01-01

    Age-related disease risk has been linked to short sleep duration and sleep disturbances; however, the specific molecular pathways linking sleep loss with diseases of aging are poorly defined. Key cellular events seen with aging, which are thought to contribute to disease, may be particularly sensitive to sleep loss. We tested whether one night of partial sleep deprivation (PSD) would increase leukocyte gene expression indicative of DNA damage responses (DDR), the senescence-associated secretory phenotype (SASP), and senescence indicator p16(INK4a) in older adult humans, who are at increased risk for cellular senescence. Community-dwelling older adults aged 61-86years (n=29; 48% male) underwent an experimental partial sleep deprivation (PSD) protocol over 4 nights, including adaptation, an uninterrupted night of sleep, partial sleep deprivation (sleep restricted 3-7AM), and a subsequent full night of sleep. Blood samples were obtained each morning to assess peripheral blood mononuclear cell (PBMC) gene expression using Illumina HT-12 arrays. Analyses of microarray results revealed that SASP (p<.05) and DDR (p=.08) gene expression were elevated from baseline to PSD nights. Gene expression changes were also observed from baseline to PSD in NFKB2, NBS1 and CHK2 (all p's<.05). The senescence marker p16(INK4a) (CDKN2A) was increased 1day after PSD compared to baseline (p<.01), however confirmatory RT-PCR did not replicate this finding. One night of partial sleep deprivation activates PBMC gene expression patterns consistent with biological aging in this older adult sample. PSD enhanced the SASP and increased the accumulation of damage that initiates cell cycle arrest and promotes cellular senescence. These findings causally link sleep deprivation to the molecular processes associated with biological aging. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. An accelerated assay for the identification of lifespan-extending interventions in Drosophila melanogaster

    PubMed Central

    Bauer, Johannes H.; Goupil, Stephan; Garber, Graham B.; Helfand, Stephen L.

    2004-01-01

    Recent advances in aging research have uncovered genes and genetic pathways that influence lifespan in such diverse organisms as yeast, nematodes, flies, and mice. The discovery of genes and drugs that affect lifespan has been delayed by the absence of a phenotype other than survivorship, which depends on the measurement of age at death of individuals in a population. The use of survivorship to identify genetic and pharmacological interventions that prolong life is time-consuming and requires a large number of homogeneous animals. Here, we report the development of an assay in Drosophila melanogaster using the expression of molecular biomarkers that accelerates the ability to evaluate potential lifespan-altering interventions. Coupling the expression of an age-dependent molecular biomarker to a lethal toxin reduces the time needed to perform lifespan studies by 80%. The assay recapitulates the effect of the three best known environmental life-span-extending interventions in the fly: ambient temperature, reproductive status, and calorie reduction. Single gene mutations known to extend lifespan in the fly such as Indy and rpd3 also extend lifespan in this assay. We used this assay as a screen to identify drugs that extend lifespan in flies. Lipoic acid and resveratrol were identified as being beneficial in our assay and shown to extend lifespan under normal laboratory conditions. We propose that this assay can be used to screen pharmacological as well as genetic interventions more rapidly for positive effects on lifespan. PMID:15328413

  19. Cerebrospinal fluid metabolomics reveals altered waste clearance and accelerated aging in HIV patients with neurocognitive impairment

    PubMed Central

    Cassol, Edana; Misra, Vikas; Dutta, Anupriya; Morgello, Susan; Gabuzda, Dana

    2014-01-01

    Objective(s): HIV-associated neurocognitive disorders (HAND) remain prevalent in HIV-infected patients on antiretroviral therapy (ART), but the underlying mechanisms are unclear. Some features of HAND resemble those of age-associated cognitive decline in the absence of HIV, suggesting that overlapping mechanisms may contribute to neurocognitive impairment. Design: Cross-sectional analysis of cerebrospinal fluid (CSF) from 100 individuals (46 HIV-positive patients and 54 HIV-negative controls). Methods: Untargeted CSF metabolite profiling was performed using liquid/gas chromatography followed by mass spectrometry. Cytokine profiling was performed by Bioplex. Bioinformatic analyses were performed in Metaboanalyst and R. Results: Alterations in the CSF metabolome of HIV patients on ART mapped to pathways associated with neurotransmitter production, mitochondrial function, oxidative stress, and metabolic waste. Many CSF metabolites altered in HIV overlapped with those altered with advanced age in HIV-negative controls, suggesting a pattern indicative of accelerated aging. Machine learning models identified neurotransmitters (glutamate, N-acetylaspartate), markers of glial activation (myo-inositol), and ketone bodies (beta-hydroxybutyric acid, 1,2-propanediol) as top-ranked classifiers of HAND. These CSF metabolites correlated with worse neurocognitive test scores, plasma inflammatory biomarkers [interferon (IFN)-α, IFN-γ, interleukin (IL)-8, IL-1β, IL-6, IL-2Ra], and intrathecal IFN responses (IFN-γ and kynurenine : tryptophan ratio), suggesting inter-relationships between systemic and intrathecal inflammation and metabolic alterations in CSF. Conclusions: Alterations in the CSF metabolome of HIV patients on ART suggest that persistent inflammation, glial responses, glutamate neurotoxicity, and altered brain waste disposal systems contribute to mechanisms involved in HAND that may be augmented with aging. PMID:24752083

  20. Predicting age-age genetic correlations in tree-breeding programs: a case study of Pinus taeda L.

    Treesearch

    D.P. Gwaze; F.E. Bridgwater; T.D. Byram; J.A. Woolliams; C.G. Williams

    2000-01-01

    A meta-analysis of 520 parents and 51,439 individuals was used to develop two equations for predicting age-age genetic correlations in Pinus taeda L. Genetic and phenotypic family mean correlations and heritabilities were estimated for ages ranging from 2 to 25 years on 31...